Hostname: page-component-78c5997874-dh8gc Total loading time: 0 Render date: 2024-11-05T09:54:38.996Z Has data issue: false hasContentIssue false

The role of vitamins and minerals in modulating the expression of microRNA

Published online by Cambridge University Press:  09 May 2014

Emma L. Beckett
Affiliation:
School of Environmental and Life Sciences, University of Newcastle, Brush Road, Ourimbah, NSW2258, Australia CSIRO Animal, Food and Health Sciences, North Ryde, NSW2113, Australia
Zoe Yates
Affiliation:
School of Biomedical Sciences and Pharmacy, University of Newcastle, Brush Road, Ourimbah, NSW2258, Australia
Martin Veysey
Affiliation:
Teaching and Research Unit, Central Coast Local Health District, PO Box 361, Gosford, NSW2250, Australia
Konsta Duesing
Affiliation:
CSIRO Animal, Food and Health Sciences, North Ryde, NSW2113, Australia
Mark Lucock*
Affiliation:
School of Environmental and Life Sciences, University of Newcastle, Brush Road, Ourimbah, NSW2258, Australia
*
*Corresponding author: Associate Professor Mark Lucock, +2 4348 4145, email mark.lucock@newcastle.edu.au
Rights & Permissions [Opens in a new window]

Abstract

A growing number of studies in recent years have highlighted the importance of molecular nutrition as a potential determinant of health and disease. In particular, the ability of micronutrients to regulate the final expression of gene products via modulation of transcription and translation is now being recognised. Modulation of microRNA (miRNA) by nutrients is one pathway by which nutrition may mediate gene expression. miRNA, a class of non-coding RNA, can directly regulate gene expression post-transcriptionally. In addition, miRNA are able to indirectly influence gene expression potential at the transcriptional level via modulation of the function of components of the epigenetic machinery (DNA methylation and histone modifications). These mechanisms interact to form a complex, bi-directional regulatory circuit modulating gene expression. Disease-specific miRNA profiles have been identified in multiple disease states, including those with known dietary risk factors. Therefore, the role that nutritional components, in particular, vitamins and minerals, play in the modulation of miRNA profiles, and consequently health and disease, is increasingly being investigated, and as such is a timely subject for review. The recently posited potential for viable exogenous miRNA to enter human blood circulation from food sources adds another interesting dimension to the potential for dietary miRNA to contribute to gene modulation.

Type
Research Article
Copyright
Copyright © The Authors 2014 

Introduction

Recently, a growing number of studies have been focusing on the interaction between nutrition and gene expression. Nutrients can interact with the genome directly (via nutrient response elements) and indirectly via modulation of mechanisms including DNA methylation, histone modification and non-coding RNA, in particular microRNA (miRNA). To date, DNA methylation and histone modifications are the best characterised of these mechanisms, with investigation into the links between nutrition and miRNA expression only being considered much more recently, and in much less depth.

Although both macro- and micronutrients can potentially modulate these mechanisms, targeting micronutrients is likely to be the most viable avenue for potential therapeutic intervention, as this avoids the confounding factor of energy provision by macronutrients. As such, the purpose of this review is to present the current scientific data suggesting that micronutrients can modulate the expression of miRNA. miRNA signatures and aberrant expression profiles have been linked to a range of disease states, including those associated with ageing, life-style and dietary factors( Reference Papageorgiou, Tousoulis and Androulakis 1 Reference Calin and Croce 3 ). Therefore, modulation of miRNA profiles may explain an additional link between molecular nutrition and phenotypes of health and disease. While the investigation of the role of miRNA in disease is not novel, investigation of the interactions between micronutrients, miRNA and disease processes is a relatively nascent area of investigation, and much remains to be elucidated.

MicroRNA

miRNA are an abundant class of short (about eighteen to twenty-three nucleotides), non-coding RNA, which are involved in post-transcriptional regulation of gene expression. The first description of a miRNA was that of lin-4 in Caenorhabditis elegans by Lee et al. in 1993( Reference Lee, Feinbaum and Ambros 4 ). Following the identification of multiple similar small regulatory RNA in plants and animals, the term microRNA was coined( Reference Ruvkun 5 ). To date, over 2000 mature human miRNA have been identified (MiRBase, release 20, June 2013; http://www.mirbase.org); however, the specific function of the majority of these has not yet been ascertained.

Due to their small size, each miRNA may target hundreds of messenger RNA (mRNA)( Reference Selbach, Schwanhausser and Thierfelder 6 ). Likewise, each mRNA can be targeted by multiple miRNA, allowing complex and multifaceted regulatory networks( Reference Brennecke, Stark and Russell 7 ). It has been estimated that miRNA have a post-transcriptional regulatory influence on more than half of all human mRNA( Reference Friedman, Farh and Burge 8 ). As such, they are believed to participate in almost all cellular processes.

A majority of investigations have centred on the role of miRNA in cancers( Reference Calin and Croce 3 ); however, aberrant miRNA expression profiles have been identified in a range of conditions including asthma( Reference Ariel and Upadhyay 9 ), CVD( Reference Papageorgiou, Tousoulis and Androulakis 1 ), autoimmune disease( Reference Wang, Peng and Ouyang 10 ) and diabetes( Reference Lorenzen, Kumarswamy and Dangwal 2 ). Unique signatures have been identified in diseased tissues (relative to adjacent healthy tissue or healthy control subjects( Reference Calin and Croce 3 )) and, more recently, plasma and serum miRNA signatures have been connected to particular disease states (for a review, see Weiland et al. ( Reference Weiland, Gao and Zhou 11 )). These circulating miRNA are promising objective and non-invasive biomarkers for disease diagnosis and prognosis, and potentially even nutritional status. Circulating miRNA offer many potential advantages as biomarkers. Circulating miRNA can be detected in blood with high levels of specificity and sensitivity, and are remarkably stable. As such, they are practical biomarkers detecting or staging a wide range of pathological processes( Reference Gilad, Meiri and Yogev 12 ). However, additional research is needed to unravel the complex miRNA profiles associated with pathophysiological conditions before this promise is fully realised.

The biogenesis and complex action of miRNA have been comprehensively reviewed elsewhere( Reference Bartel 13 , Reference Patil, Zhou and Rana 14 ) and details are outside the scope of the present review. Briefly, miRNA (as part of the RNA-induced silencing complex; RISC) act on mRNA via complementary base pairing, usually to repress translation or to increase the degradation of the target mRNA (Fig. 1). In cases of near-complete miRNA–mRNA complementarity, the target mRNA may be directly cleaved by argonaute proteins( Reference Yekta, Shih and Bartel 15 , Reference Davis, Caiment and Tordoir 16 ). More commonly, partial complementarity results in modifications that repress translation or reduce the stability of the target mRNA( Reference Chendrimada, Finn and Ji 17 Reference Wu, Fan and Belasco 19 ). Interestingly, more recent reports have demonstrated a capability of miRNA to activate target translation under specific conditions, such as during cell-cycle arrest( Reference Vasudevan, Tong and Steitz 20 Reference Vasudevan 23 ).

Fig. 1 MicroRNA (miRNA) mechanisms of action. miRNA can act by (a) blocking gene transcription or (b) inducing miRNA instability or degradation. mRNA, messenger RNA; RISC, RNA-induced silencing complex.

MicroRNA in epigenetics

The definition of epigenetics is often varied and is continuously evolving( Reference Weichenhan and Plass 24 ). It remains a matter of contention as to whether miRNA themselves are technically a component of the epigenome, or a complementary player. Most generally, epigenetics is defined as heritable changes in gene expression that do not involve a change in DNA sequence( Reference Chuang and Jones 25 Reference Sato, Tsuchiya and Meltzer 27 ). Under this broad description, if gene expression is regarded as the generation of a finally functional protein product of a gene, and not merely transcription of a gene, it is possible to argue for the inclusion of miRNA in the definition of epigenetics. However, others specify that the consensus definition of an epigenetic trait is a phenotype resulting from changes to the chromosome, in the absence of any alteration to the DNA sequence( Reference Berger, Kouzarides and Shiekhattar 28 ). Under this definition it is impossible to include miRNA in the epigenome, as their gene-regulation potential occurs post-transcriptionally. In this context, miRNA have been described as epigenetic ‘initiators’( Reference Berger, Kouzarides and Shiekhattar 28 ).

Regardless of whether miRNA are positioned within or peripheral to the definition of epigenetics, the two are inextricably linked( Reference Weichenhan and Plass 24 ). miRNA and the epigenome can regulate each other, as well as act in concert, forming a complex bi-directional epigenetics–miRNA regulatory circuit. Importantly, miRNA and other epigenetic modifications are all plastic in response to stimuli, such as environmental exposures and endogenous signalling. This ultimately allows unique phenotypes to stem from one genotype( Reference Park, Friso and Choi 29 ) via modification of gene expression potential( Reference Jaenisch and Bird 30 ).

Common epigenetic modifications can be classified as DNA methylation and histone modifications. DNA methylation is the most extensively studied epigenetic trait. DNA methylation occurs when methyl groups are added to the DNA sequence, normally at a CpG dinucleotide. Methylation in the promoter or other regulatory regions of a gene is usually associated with gene silencing( Reference Deaton and Bird 31 ). Multiple histone modifications (including acetylation, phosphorylation, ubiquitination and methylation of histone protein tails) can occur that regulate the transcription level of genes( Reference Das and Tyler 32 ). Importantly, none of these processes occurs independently and it is the sum of all of these marks, referred to as the epigenome, that modulates gene expression.

These mechanisms are important in normal processes, especially those that occur during development and ageing, but can also drive pathophysiological processes. It is thought that the modification of epigenetic marks on the genome explains how environmental and life-style factors can modify an individual's risk of developing certain diseases( Reference Park, Friso and Choi 29 ). The plasticity of epigenetic marks has led to significant interest in manipulation of the epigenome for therapeutic purposes( Reference Costello, Krzywinski and Marra 33 , Reference Christensen, Houseman and Marsit 34 ). miRNA are deeply involved in the epigenome. Not only can they directly modulate gene expression post-transcriptionally, but several miRNA (known as epi-miRNA) have been identified that directly influence the function of the other components of the epigenetic machinery( Reference Fabbri and Calin 35 ). This, in turn, indirectly influences the epigenetic modulation of other genes (Fig. 2). Potential nutritional regulators have been identified for some of these epi-miRNA (Table 1). Conversely, miRNA expression can also be regulated by classical epigenetic mechanisms (methylation and histone modifications; for a review, see Sato et al. ( Reference Sato, Tsuchiya and Meltzer 27 )) and expression of one miRNA may also regulate expression of another miRNA( Reference Martello, Rosato and Ferrari 36 ). The interaction and overlapping of these two mechanisms allow for regulation of miRNA levels and thus their genetic targets via complex feedback loops.

Fig. 2 Summary of the potential effects of vitamins and minerals on gene expression. MicroRNA (miRNA) are intrinsically involved in gene regulation. Vitamins and minerals can induce the expression of miRNA via the activation of transcription factors/response elements, leading to altered gene expression by the induction of messenger RNA (mRNA) degradation or the repression of translation. Vitamins and minerals may also alter the function of the classical epigenetic machinery, altering expression of DNA methyltransferases (DNMT) and histone modification enzymes, such as histone deacetylases and histone acetyltransferases. Modulation of these enzymes leads to changes in DNA methylation status and histone modifications, which in turn can modulate the expression of other genes, including miRNA themselves. These interconnecting pathways allow for the modulation of complex processes and feedback loops.

Table 1 Epigenetic microRNA with identified vitamin or mineral regulators

DNMT, DNA-methyl transferase; HDAC, histone deacetylase; HAT, histone acetyltransferase.

Several miRNA loci have been shown to be differentially methylated in a range of cancers( Reference Lujambio, Calin and Villanueva 37 Reference Guan, Yin and Li 40 ). Examples of aberrant methylation of miRNA loci include miR-9-1 in breast cancer( Reference Lehmann, Hasemeier and Christgen 41 ) and miR-1 in hepatocellular carcinoma( Reference Datta, Kutay and Nasser 42 ). Treatment of the cancer cell line T24 with a DNA methylation inhibitor (5-aza-2′-deoxycytidine) resulted in increased expression of miR-126, -132 and -205( Reference Saito, Liang and Egger 39 ), suggesting that these miRNA were previously inhibited by methylation. Epigenetic drugs, targeting DNA methylation and histone modifications, are currently undergoing clinical trials and some have been approved by the Food and Drug Administration and the European Medicines Agency( Reference Nebbioso, Carafa and Benedetti 43 ). These interventions are likely to make an impact upon miRNA profiles and, as such, studies are needed to elucidate these treatment effects on miRNA profiles.

Treatment with histone deacetylase (HDAC) inhibitors, such as phenyl butyric acid, has also been shown to modulate miRNA profiles in multiple cancer cell lines( Reference Saito, Liang and Egger 39 , Reference Nasser, Datta and Nuovo 44 , Reference Scott, Mattie and Berger 45 ). This suggests that changes in gene expression previously attributed solely to the direct action of histone modifications may, at least in part, be due to the associated indirect effects of miRNA expression. miRNA may be involved in co-regulation or fine tuning of these processes or be a consequence of the histone modifications themselves. In particular, HDAC1 has been demonstrated to directly enhance miRNA expression by enhancing the rate of miRNA production via deacetylation of critical lysine residues in the RNA-binding domain of DGCR8 (DiGeorge syndrome critical region 8), a protein involved in miRNA biogenesis( Reference Wada, Kikuchi and Furukawa 46 ). This demonstrates that HDAC are involved in gene silencing both via transcriptional repression and by increasing miRNA abundance.

Multiple epi-miRNA have been identified that directly and indirectly target DNA-methyl transferases (DNMT), the enzymes responsible for DNA methylation( Reference Fabbri, Garzon and Cimmino 47 Reference Duursma, Kedde and Schrier 51 ) as well as the enzymes responsible for histone modifications, such as histone methyltransferases( Reference Sander, Bullinger and Klapproth 52 Reference Fan, Tsang and Tam 57 ), deacetylases( Reference Datta, Kutay and Nasser 42 , Reference Nasser, Datta and Nuovo 44 , Reference Sluijter, van Mil and van Vliet 58 Reference Buurman, Gürlevik and Schäffer 63 ) and acetyltransferases( Reference Roccaro, Sacco and Jia 64 ). These studies, in cancer and inflammatory cells, have demonstrated that aberrant expression of multiple miRNA can alter the levels of DNMT and histone-modifying enzymes. This may have implications for the role of miRNA modulation in the pathogenesis and progression of cancers and inflammatory diseases.

It is likely that as investigations continue, more examples of epi-miRNA and epigenetically regulated miRNA will be identified. Despite the general acceptance of miRNA as important regulators of gene transcription, much remains to be determined about their genetic and environmental modulation and their consequences for health, disease and longevity. As several dietary factors are known to influence the epigenome, modulation of miRNA profiles via dietary stimuli warrants further discussion.

Nutritional modulation of epigenetic traits

Whilst the epigenome is plastic in response to stimuli, modifications may also persist long after the cessation of exposure. The role of epigenetics in underpinning the developmental origins of disease (the Barker hypothesis), which suggests that events occurring in utero can predispose to disease such as coronary artery disease and diabetes later in life( Reference Barker 65 Reference Barker, Winter and Osmond 67 ), is now being recognised( Reference Canani, Costanzo and Leone 68 ). Differential methylation of disease-related genes have been identified in adults conceived during the Dutch famine of the Second World War, compared with their siblings conceived outside of famine( Reference Tobi, Slagboom and van Dongen 69 Reference Heijmans, Tobi and Stein 71 ). Additional analyses of other epigenetic traits, including the role of miRNA in this population, are likely to be informative.

Studies of monozygotic twins have shown that differences in epigenetic traits appear to become more pronounced with ageing and divergence of life-style( Reference Fraga, Ballestar and Paz 72 Reference Zhao, Goldberg and Vaccarino 75 ). As such, it is now realised that developmental and epigenetic plasticity extends beyond the pre- and postnatal periods and into later life. Ageing, genetics and environmental (including nutritional) influences all make an impact upon epigenetic regulation, with environmental influences the only practical point for intervention. As there are optimal nutritional requirements for maintaining the metabolome, and nutritional status has an impact upon physiology throughout life, nutrition clearly forms a significant environmental component( Reference Park, Friso and Choi 29 ).

Diet is therefore one of the most important modifiable determinants of risk in many diseases, with the phenotypic outcomes of adverse dietary habits accumulating over a lifetime. Chronic diseases or diseases with age-related onset, such as cancer, CVD and diabetes, are particularly well recognised as having associated life-style risk factors, in particular dietary components( Reference Roberts and Barnard 76 , 77 ). Diet also plays an additional ongoing role in disease, as patients suffering from chronic diseases may have impaired nutritional status as a consequence of disease( Reference Teunissen, Wesker and Kruitwagen 78 ). Roles for both dietary factors and miRNA have been identified in the functioning and modification of multiple disease-related pathways including DNA methylation, inflammation, cell-cycle repair, apoptosis and DNA repair. This has led to expanding investigations into the relationships between miRNA signatures, dietary habits and disease risk.

Modulation of microRNA expression by micronutrients

Manipulation of miRNA profiles through dietary modifications and supplements has been proposed as a potential future therapeutic intervention or prevention strategy( Reference Witwer 79 Reference McKay and Mathers 81 ). While both macronutrients and micronutrients have been identified as potential disease and miRNA modifiers, micronutrients may represent the preferred intervention path, as this avoids the confounding role that macronutrients play in energy provision. Intervention, whether through dietary modifications or supplementation, may offer novel therapeutic strategies for a host of conditions. Despite the clear opportunities for novel preventative and therapeutic strategies, investigation into the dietary modulation of miRNA profiles remains in its infancy. To date, limited studies have been conducted in human cohorts, with the majority of studies conducted in cell systems or animal models. Details of known associations between miRNA and vitamins and minerals are summarised in online Supplementary Table S1 and described below.

Vitamin D

Vitamin D is a fat-soluble steroid vitamin and pro-hormone that can be consumed in the diet as cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2), or synthesised by the skin in response to sunlight. In addition to its classical role in maintaining bone health and Ca homeostasis, epidemiological evidence has now identified a potential role for vitamin D deficiency in a range of conditions including diabetes( Reference Pittas, Lau and Hu 82 ), CVD( Reference Wang, Pencina and Booth 83 ), autoimmune disease( Reference Adorini 84 ) and some cancers( Reference Lappe, Travers-Gustafson and Davies 85 ). Vitamin D supplementation is now being investigated in the treatment and prevention of these diseases, with a particular focus on its potential as a cancer chemopreventative, due to the identified role of the vitamin D receptor (VDR) in cell-cycle regulation and differentiation( Reference Lamprecht and Lipkin 86 ).

The active vitamin D metabolite, calcitriol (1,25-dihydroxyvitamin D3), has long been known to directly regulate gene transcription via interaction with the VDR, which acts as a nuclear receptor transcription factor( Reference Carlberg 87 ). However, post-transcriptional regulatory mechanisms for vitamin D have also been proposed. Regulation of mRNA levels via miRNA signalling is now becoming recognised as a potential additional mechanism for action for vitamin D, and consequences of these interactions are now being investigated( Reference Sonkoly, Lovén and Xu 88 , Reference Giangreco, Vaishnav and Wagner 89 ).

Abnormal proliferation is a signature feature of cancer cells. Vitamin D has been demonstrated to suppress proliferation in multiple malignant cell lines( Reference Essa, Reichrath and Mahlknecht 90 Reference Mohri, Nakajima and Takagi 93 ). In colon cancer cell lines (SW80-ADH and HCT116) the anti-proliferative effects of calcitriol treatment correlated with an induction of miR-22, -146a and -222 expression, and a reduction in miR-203 expression. miR-203 is a known suppressor of the proto-oncogene JUN ( Reference Sonkoly, Lovén and Xu 88 ). miR-222 and -22 are known epi-miRNA, targeting DNMT3 and HDAC4, respectively( Reference Zhang, Yang and Yang 94 , Reference Lee, Jeong and Lim 95 ). In particular, miR-22 expression was found to be induced in a dose-, time- and VDR-dependent manner. Moreover, miR-22 expression has also been shown to be lower in human colon cancer tissue, compared with surrounding normal tissue, correlating with changes in VDR expression levels( Reference Alvarez-Díaz, Valle and Ferrer-Mayorga 92 ). This suggests that miR-22 may have an anti-cancer effect that is modulated by vitamin D and the VDR. However, in another colorectal cancer cell line (HT-29 cells), miR-627 was the only miRNA significantly up-regulated by calcitriol treatment. Blocking miR-627 inhibited the anti-proliferative effects of calcitriol treatment. miR-627 targets Jumonji domain containing 1A (JMJD1A), which encodes a histone demethylase( Reference Padi, Zhang and Rustum 96 ).

Additional anti-cancer properties of vitamin D have been investigated in a range of cancer cell lines. Treatment of promyeloblastic leukaemia (HL60) and pro-monocytic leukaemia (U937) cells with low concentrations of calcitriol led to decreased expressions of miR-181a and -181b, in a dose- and time-dependent manner, and the arrest of cell-cycle progression in the G1 phase. Transfection of pre-miR-181a blunted these effects. Treatment of prostate cancer cell lines (RWPE-1, RWPE-2, PrEC and PrE) with calcitriol led to a significant up-regulation of the tumour-suppressor miRNA miR-100 and -125b( Reference Giangreco, Vaishnav and Wagner 89 ). In LNCaP prostate cancer cells, calcitriol treatment induced expression of miR-98, a tumour-suppressor miRNA, and suppressed proliferation. This occurred both via direct induction due to the enhanced binding of VDR to the vitamin D response element (VDRE) in the miR-98 promoter region, and indirectly via down-regulation of gene expression( Reference Ting, Messing and Yasmin-Karim 97 ). VDR–VDRE interaction has also been shown to up-regulate let-7a-2 expression in human lung cancer cells (A549 cells)( Reference Guan, Liu and Chen 98 ). Despite the diversity of the miRNA involved, these results suggest that aberrant expression of miRNA may contribute to the malignant phenotype and that this can be moderated by vitamin D treatment( Reference Wang, Gocek and Liu 99 ).

Vitamin D is also believed to play a role in protection from cellular stress. In a study using a breast epithelial cell line (MCF12F), calcitriol treatment protected cells against death in models of starvation, oxidative stress, hypoxia and apoptosis induction. Serum starvation led to significant increases in the expression of multiple miRNA (including miR-26b, -182, -200b/c, and the let-7 family). However, this was reversed in the presence of calcitriol, indicating that miRNA expression may be a mechanism that protects against cellular stress via a vitamin D-related process( Reference Peng, Vaishnav and Murillo 100 ). This may have implications in multiple disease states including diabetes, CVD and cancers( Reference Fulda, Gorman and Hori 101 ).

Although the evidence generated in cell studies suggests a role for miRNA and vitamin D in modulating disease-related processes, these studies often used supra-physiological doses. Furthermore, limited studies involving correlation between serum levels of vitamin D and miRNA expression in human subjects have been conducted. In a study of forty subjects given oral vitamin D supplementation for 12 months compared with thirty-seven receiving placebo, serum miRNA and vitamin D levels were measured at baseline and post-supplementation. At baseline a positive correlation was detected between serum 25-hydroxyvitamin D levels and miR-532-3p expression. miR-532-3p has been shown to target the gene for glucose-6-phosphatase, an important enzyme in glucose homeostasis( Reference Jia, Cong and Li 102 ). After 12 months of supplementation there was a significant difference in the expression of miR-221; however, this was due to a decrease in levels in the control, rather than the experimental, group( Reference Jorde, Svartberg and Joakimsen 103 ), possibly indicating that vitamin D deficiency in the placebo group led to the change in miR-221 expression.

In a study of pregnant women, plasma calcitriol was measured and patients were categorised as either low ( ≤ 25.5 ng/ml) or high ( ≥ 31.7 ng/ml)( Reference Enquobahrie, Williams and Qiu 104 ). Respectively, these groups reflect deficiency and sufficiency( Reference Nowson, McGrath and Ebeling 105 ). A total of eleven miRNA were differentially regulated (ten down and one up) in the low group compared with the high group. However, this study was of limited power, as only thirteen subjects were assayed and no functional conclusions were drawn( Reference Enquobahrie, Williams and Qiu 104 ).

Folate and related vitamins involved in methyl group metabolism

Folate (as the 5-methyltetrahydrofolate vitamer), methionine, choline and vitamin B12 are critical in one-carbon metabolism, which is the major source of methyl donors for cellular methylation reactions. These reactions include the essential processes of DNA synthesis and repair, DNA methylation, cell proliferation and the synthesis of amino acids( Reference Lucock 106 ). Folate can be used in the de novo generation of methionine and, as such, consumption of folate and other methyl group donors dictates the availability of methyl groups for use in methylation reactions. Therefore, folate and other methyl group donor levels may influence miRNA profiles indirectly via alteration of DNA methylation states, or may have an impact on miRNA expression levels through other methylation reactions. Low folate consumption has been associated with increased risks of birth defects, CVD, depression, hearing loss, and some cancers, particularly breast, colon, pancreatic and stomach( Reference Lucock 106 , Reference Lucock and Daskalakis 107 ).

Folate-deficient mouse embryonic stem cells have been shown to have inhibited growth, and a significantly higher rate of apoptosis. Multiple miRNA (let-7a, miR-15a, -15b, -16, -29a, -29b, -34a, -130b, -125a-5p, -124, -290 and -302a) were confirmed to be differentially expressed during folate deficiency( Reference Lianga, Lib and Liub 108 ). A similar magnitude of modulation has been demonstrated in human cell lines. Exposure of the human lymphoblast cell line TK-6 to folate-deficient media for 6 d led to a significant modulation of expression of twenty-four different miRNA. Importantly, return of these cells to folate-sufficient media led to a restoration of miRNA profiles to control levels( Reference Marsit, Eddy and Kelsey 109 ). Of particular interest in this study was the up-regulation of the epi-miRNA miR-222 and -22 under folate-deficient conditions. This in vitro result was complemented by the demonstration of higher levels of both these miRNA in human blood taken from patients in the lowest percentile for folate intake, compared with those in the highest percentile( Reference Marsit, Eddy and Kelsey 109 ). However, this study was conducted in a subset of patients from a larger case–control study of head and neck squamous cell carcinoma, which may be a confounding factor, and only included eleven subjects in total( Reference Marsit, Eddy and Kelsey 109 ).

Research on folate deficiency in animal models has centred on the role of methyl groups in hepatic cancer. Several animal models have demonstrated disease consequences of methyl group deficiency and have linked these to aberrant miRNA expression profiles. A methyl donor-deficient diet in rats leads to hepatocellular carcinoma (HCC) after 54 weeks( Reference Tryndyak, Ross and Beland 110 Reference Kutay and Bai 112 ). Comparison of miRNA microarray profiles in liver tissue from rats fed this diet showed an increased expression of let-7a, miR-21, -23, -130, -190 and -17-92, and decreased miR-122, compared with rats fed the control diet( Reference Kutay and Bai 112 ). This adds weight to the changes in let-7a and miR-130b expression seen in cell-culture models. Interestingly, when the diet was returned to the control regimen at 36 weeks, miR-122 levels returned to normal and HCC did not develop( Reference Kutay and Bai 112 ).

Further analysis of this rat model identified profound down-regulation of miR-34a, -16a, -181a, -200b and -127, all of which are known tumour-suppressor miRNA. Notably, suppression of miR-34a and -127 occurred early and continued throughout carcinogenesis. This correlated with increased levels of E2F3 (E2F transcription factor 3) and BCL6 (B-cell lymphoma 6), proteins known to be regulated by miR-34a and − 127, respectively( Reference Tryndyak, Ross and Beland 110 , Reference Pogribny, Tryndyak and Ross 113 ).

In a murine model of a choline-deficient and amino acid-defined diet, hepatocarcinogenesis is usually induced after approximately 84 weeks( Reference Wang, Majumder and Nuovo 114 ). The oncogenic miR-155, -221, -222 and -21 were shown to be up-regulated in hepatic tissue in this model. This correlated with a significant reduction in the expression of the tumour-suppressor genes hepatic phosphatase and tensin homologue (PTEN) and CCAAT/enhancer binding protein β (C/EBPB), which are targets of miR-21 and -155, respectively. Furthermore, the expression of miR-155, as measured by in situ hybridisation and real-time RT-PCR, correlated with diet-induced histopathological changes in the liver( Reference Wang, Majumder and Nuovo 114 ).

Given the link between dietary methyl group donors and regulation of DNA methylation, and the miRNA listed above, further investigation into epigenetic regulation of miRNA and the impacts upon their targets is clearly warranted.

Retinoic acid

Retinoic acid, a metabolite of vitamin A (retinol), is important in growth and development. Like vitamin D, most of its known functions are mediated through binding to nuclear receptors and subsequent modification of gene transcription. Retinoic acid acts by binding to the retinoic acid receptor (RAR), forms a heterodimer with the retinoid X receptor (RXR) and binds to DNA in regions known as retinoic acid response elements. Binding of the retinoic acid ligand to RAR alters its conformation, affecting the binding of other proteins that either induce or repress transcription of nearby genes – including the developmentally significant transcription factors coded for by Hox genes and several other target genes( Reference Duester 115 ). However, modulation of miRNA profiles is now under investigation as an additional mechanism of action.

Retinoic acid is known to modulate neural differentiation and is used in neuroblastoma therapies, where a potential role for miRNA has been identified. In NT-2 (human embryonic carcinoma) cells, differentiation into neural cells is induced by treatment with retinoic acid. However, when miR-23 expression is knocked down with a small interfering RNA, this process does not occur, indicating a mechanistic role for miR-23 in the differentiation process( Reference Kawasaki and Taira 116 ). Treatment of neuroblastoma cell lines with retinoic acid leads to cellular differentiation and inhibits proliferation( Reference Annibali, Gioia and Savino 117 Reference Beveridge, Tooney and Carroll 119 ). miR-9 and -103a are both up-regulated in these cells following treatment. Both of these miRNA target ID2, a transcription factor expressed in neural precursor cells, but also up-regulated during tumorigenesis in the neural system( Reference Annibali, Gioia and Savino 117 ). Conversely, retinoic acid has also been shown to down-regulate miR-9, -124a and -125b expression in spinal tissue in a rodent model of spina bifida, suggesting that these miRNA may be involved in the modulation of embryonic spinal development( Reference Zhao, Sun and Wang 120 ). This may demonstrate differential expression in different tissues and environments, and highlights the need for further study.

Retinoic acid treatment of neuroblastoma cell lines has also been shown to lead to an increased expression of miR-152, which has been shown to target DNMT1. Over-expression of miR-152 in SK-N-BE cells mimicked some, but not all, of the features of differentiation seen with retinoic acid treatment, suggesting that miR-152 is only partially responsible for phenotype in this system( Reference Das, Foley and Bryan 118 ). The miR-17 family has been identified as down-regulated in retinoic acid-induced differentiation of neuroblasts( Reference Beveridge, Tooney and Carroll 119 ). miR-7 has been shown to be a regulator of both proliferative and anti-proliferative genes, possibly via the regulation of the mitogen-activated protein kinase (MAPK) signalling pathway( Reference Beveridge, Tooney and Carroll 119 , Reference Cloonan, Brown and Steptoe 121 , Reference Yang, Yin and Wang 122 ). This demonstrates a potential role for miR-17 in conjunction with other miRNA in the complex control of neuronal differentiation.

Retinoic acid induces granulocytic differentiation in leukaemia cell lines. In HL-60 cells, treatment with all-trans-retinoic acid (ATRA) modulates the expression of multiple miRNA, including the up-regulation of miR-29a, -142-3p( Reference Wang, Gong and Yu 123 ), -663, -494, -145, -22, -363* and -223( Reference Jian, Li and Fang 124 ). The findings for miR-29a and -142-3p were replicated in THP-1 and NB4 cells. Additionally, forced expression of either miRNA in haematopoietic stem cells from healthy controls and acute myeloid leukaemia (AML) patients promoted myeloid differentiation. This suggests that miR-29a and -142-3p are key regulators of normal myeloid differentiation and their reduced expression is involved in AML development( Reference Wang, Gong and Yu 123 ).

Treatment of NB4 and primary cells from acute promyelocytic leukaemia patients with ATRA up-regulated the expression of let-7d/a-3, miR-223, -107, -15a and -16-1, which is also negatively correlated with Bcl-2 (B-cell lymphoma 2) and Ras protein expression( Reference Garzon, Pichiorri and Palumbo 125 ). miR-16-1 and let-7a transfection demonstrated that these miRNA targeted the genes BCL-2 and RAS, respectively. Bcl-2 is a regulator of apoptosis and Ras regulates a range of cellular processes. Furthermore, the recruitment of NF-κB on the let-7a-3/let-7b cluster promoter upon treatment with retinoic acid suggests that this is the mechanism of regulation of miRNA expression in this case( Reference Garzon, Pichiorri and Palumbo 125 ). Conversely, authors of a later study of ATRA differentiation in NB4 cells reported that let-7a was down-regulated following ATRA treatment( Reference Rossi, D'Urso and Gatto 126 ). This apparent contradiction is probably due to the differences in culture time used in the two experiments (48 h( Reference Garzon, Pichiorri and Palumbo 125 ), compared with 6 d( Reference Rossi, D'Urso and Gatto 126 )). This highlights the importance of the temporal specificity of the relationships between nutrients, miRNA expression and physiological consequences and this needs to be considered in furthering these studies.

Vitamin C

Vitamin C (ascorbate, dehydroascorbate and monodehydroascorbate) is a cofactor in multiple biological processes, including collagen synthesis, neurotransmitter synthesis and hormonal activation. Vitamin C deficiency is perhaps best known for causing scurvy. Vitamin C is also an antioxidant molecule and as such it has been suggested to have a positive impact on CVD, hypertension, chronic inflammatory disease and diabetes. However, evidence for its health benefits is still inconclusive and further long-term studies are required( Reference Juraschek, Guallar and Appel 127 Reference Riccioni, Frigiola and Pasquale 129 ).

Limited investigations have occurred into the influence of vitamin C on miRNA profiles, and none yet has targeted the disease states listed above. miRNA profiles in response to vitamin C status have, however, been investigated in hormonal regulation and cell differentiation. In periodontal ligament cells (a multi-potent cell population) treatment with ascorbic acid induced cellular differentiation and an increase in miR-146 expression. Stimulation of these cells with miR-146 alone led to the induction of differentiation( Reference Hung, Chen and Kuang 130 ). In mice deficient in the enzyme l-gulono-γ-lactone oxidase (unlike humans, mice can normally synthesise ascorbic acid in a pathway dependent on this enzyme) cells have reduced capacity to oppose oxidative stress( Reference Kim, Ku and Rosenwaks 131 ). In murine ovarian follicular cells, this corresponds with higher levels of let-7b, miR-16, -30a, -126, -143, -322 and -721 and lower levels of let-7c. The cause and consequence of these changes are yet to be identified, but suggest a potential role for vitamin C in regulating the target genes of these miRNA in developmental and maturation processes( Reference Kim, Ku and Rosenwaks 131 ). As the role of antioxidants such as vitamin C in chronic disease is further investigated, there is potential for additional roles for vitamin C in modulation of miRNA expression to be identified.

Vitamin E

Vitamin E belongs to a fat-soluble group of vitamins that includes several vitamers belonging to the tocopherols and tocotrienols. Vitamin E has multiple biological functions, including its role as a major lipid-soluble antioxidant, and, unlike many other vitamins, it is not an enzyme cofactor. A major role for vitamin E has also been identified in the regulation of gene expression in some instances. An inverse association between l-α-tocopherol (the major biologically active vitamer of vitamin E) intake and some cancers has been reported in multiple studies( Reference Woodson, Tangrea and Barrett 132 Reference Zhang, Shu and Li 137 ). However, not all studies have drawn the same conclusions, with others finding a neutral( Reference Ocké, Bueno-de-Mesquita and Feskens 138 , Reference Gilbert, Metcalfe and Fraser 139 ) or detrimental effect on cancer and heart disease risk( Reference Lonn, Bosch and Yusuf 140 , Reference Miller, Pastor-Barriuso and Dalal 141 ). This lack of consensus may be due to a significant variance in the doses tested – a 2005 meta-analysis found that studies used a range of doses from 16.5 to 2000 IU/d( Reference Miller, Pastor-Barriuso and Dalal 141 ).

The impact of dietary α-tocopherol on miRNA expression has been investigated in a rodent model of vitamin E deficiency. miR-122 and -125b were selected for assessment due to their known roles in lipid metabolism, cancer progression and inflammation. Vitamin E deficiency resulted in decreased levels of both miR-122 and -125b, as well as reduced plasma cholesterol levels( Reference Rimbach, Moehring and Huebbe 142 ). Synthetic inhibition of miR-122 in mice led to the increased expression of 108 genes related to lipid metabolism and led to a significant reduction of plasma cholesterol( Reference Esau, Davis and Murray 143 , Reference Elmén, Lindow and Silahtaroglu 144 ). Although the effects of vitamin E depletion are not as strong as targeted inhibition, these studies suggest that vitamin E regulates gene expression at the post-transcriptional level through miRNA modulation; however, the gene and transcription factor targets are yet to be validated.

Selenium

Se is an essential nutrient found in Brazil nuts, shellfish, chicken, organ meats, game meat and beef. It exists in a range of chemical forms, including: selenomethionine, selenocysteine, selenate, selenoneine and selenite. Se has structural and enzymic biological roles, pro-apoptotic and DNA repair properties and is an important cofactor in the production and activity of antioxidant enzymes. Se is vital for human health and deficiencies have been linked to various diseases including cancers, autoimmune disease and CVD( Reference Rayman 145 ).

Association studies have suggested links between low Se status, cognitive decline, immune disorders and increased mortality. High Se levels appear to be beneficial in some cancer types, but the results of supplementation intervention trials have been mixed, suggesting that supplementation is only beneficial if dietary intake is inadequate( Reference Rayman 145 ). Some studies have suggested a positive correlation between Se status and risk of type 2 diabetes; however, other studies have shown no correlation( Reference Rayman, Blundell-Pound and Pastor-Barriuso 146 Reference Laclaustra, Navas-Acien and Stranges 148 ).

miRNA modulation is a potential mechanism of action for Se; however, it is clear that additional empirical evidence is required to elucidate the potential of Se as a nutraceutical. Treatment of LNCaP human prostate cancer cells with selenite, a natural form of Se, has been shown to induce an up-regulation of p53 expression which occurs in parallel with an up-regulation of miR-34b/c( Reference Sarveswaran, Liroff and Zhou 149 ). The miR-34 is family known to target the p53 gene( Reference Hermeking 150 ) and this finding suggests that this miRNA family plays a role in modulation of the cell cycle in the induction of cancer. Despite this, further investigation is needed to determine the target of Se-induced miR-34 and any additional miRNA that may be influenced by Se status.

Zinc

Zn is required for numerous structural, catalytic and regulatory functions. Deficiency has been linked to growth retardation, dermatitis, taste impairment, delayed puberty, haematological abnormalities and immune dysfunction( Reference Prasad 151 ). In a study using varied dietary intakes of Zn (acclimatisation, depletion and repletion) in healthy adult males, nine miRNA were identified in plasma that were sensitive to plasma Zn concentrations. miR-10b, -155, -200b, -296-5p, -373, -92a, -145, -204 and -211 were all reduced in abundance during the depletion phase of the diet and increased during the repletion phase. Depletion corresponded to a compromised ability of blood cells to produce the inflammatory cytokine TNFα in response to inflammatory stimuli( Reference Ryu, Langkamp-Henken and Chang 152 ). The consequences of the modulation of the miRNA profile may in fact be more extensive and require further investigation.

Iron, magnesium and aluminium

Treatment of microglial cells with Fe and aluminium sulfate, aluminium sulfate alone, but not Fe sulfate alone has been shown to up-regulate miR-125b and -146a expression, via an NF-κB-dependent mechanism. These miRNA are involved in astroglial cell proliferation and inflammatory responses, respectively, and are significantly up-regulated in Alzheimer's disease( Reference Pogue, Percy and Cui 153 ). Modulation of specific miRNA by Fe alone has yet to be demonstrated; however, an important role for ferric haem has been demonstrated in the modulation of the miRNA processing machinery. DGCR8 forms a highly stable and active complex with ferric haem. When reduced to the ferrous state, the primary transcript (pri)-miRNA-processing capacity of the DGCR8 complex is abrogated( Reference Barr, Smith and Chen 154 ).

Likewise, Mg has been shown to interact with the miRNA-processing machinery, with RISC (RNA-induced silencing complex) being an Mg2+-dependent protein. Mg ions are also located at the small RNA-binding domain of the argonaute protein and are important for sequence-specific miRNA–target interactions, contributing to the binding of miRNA to the argonaute protein and thus playing a role in the cleavage of miRNA targets. Mg ions have also been shown to modulate the global stabilisation of the argonaute protein( Reference Ma, Xue and Zhang 155 ).

Direct uptake of microRNA from foods

It has recently been suggested that diet may have an even more direct impact upon miRNA profiles. The plant and animal foods included in our diet also contain miRNA that may be taken up into the body upon consumption, and as such may remain biologically active. If this is possible, then sequence homology could potentially allow regulation of endogenous genes by miRNA acquired from dietary sources( Reference Zhang, Hou and Chen 156 ). Previously, this cross-taxonomic regulation by small RNA had been demonstrated in a variety of model systems, including bacteria, viruses and worms( Reference Newmark, Reddien and Cebrià 157 Reference Omarov and Scholthof 159 ). miRNA are also secreted in human breast milk and cows' milk, and may serve as a route of biological communication through feeding( Reference Zhou, Li and Wang 160 Reference Kosaka, Izumi and Sekine 162 ).

Exogenous miRNA may originate from multiple sources. Plant miRNA remain detectable, although some at reduced levels, in cooked wheat, rice and potatoes( Reference Zhang, Hou and Chen 156 ). It has also been reported that the miRNA in cows' milk are stable under conditions that would normally be considered degenerative for miRNA( Reference Izumi, Kosaka and Shimizu 161 ). In future studies this needs to be verified for other foods and cooking conditions (methods, temperatures and times). It is hypothesised that other components of food, such as cholesterol and protein, may protect miRNA from degradation( Reference Jiang, Sang and Hong 163 ).

The first suggestion of the uptake of exogenous miRNA from food in humans has only recently been published. In 2012, Zhang et al. ( Reference Zhang, Hou and Chen 156 ) described in a study ten pools of serum from thirty healthy Chinese adults that almost thirty plant miRNA were detectable in serum, albeit at much lower levels than endogenous miRNA. Two of these, miR-156a and -168, are detectable in high levels in rice and crucifers, which are staple foods in the Chinese diet. Additionally, mice fed rice were reported to have elevated serum and tissue levels of miR-156a and -168, compared with those fed a standard mouse chow diet after 6 h. Furthermore, oral administration of mice with miR-168a isolated from fresh rice, synthetic miR-168a, or methylated synthetic miR-168 all led to increases in miR-168a levels in the serum and liver 3 h post-oral administration( Reference Zhang, Hou and Chen 156 ).

However, these findings are yet to be independently replicated, and others have since presented conflicting studies. It has now been suggested that there is in fact limited evidence for the general dietary uptake of exogenous miRNA from plants and questions have been raised regarding this hypothesis( Reference Witwer, McAlexander and Queen 164 , Reference Snow, Hale and Isaacs 165 ). After feeding a plant miRNA-rich substance to two pigtailed macaques, plant miRNA were only detected in plasma in some assays, at very low, and possibly non-specific levels and did not shift substantially from baseline following consumption of the plant miRNA-rich substance( Reference Witwer, McAlexander and Queen 164 ). Additional feeding studies high in exogenous miRNA in human subjects, mice and bees were also unable to detect significant levels of endogenous miRNA( Reference Snow, Hale and Isaacs 165 ). A study of publicly available small RNA datasets concluded that while plant RNA was identified in animal samples, this detection was at a low level and probably due to a sequencing artifact or external contamination( Reference Zhang, Wiggins and Lawrence 166 ). These studies suggest that the dietary uptake of miRNA is at best limited and may not be robust.

Furthermore, it has been suggested that the quantities of exogenous miRNA that would need to be ingested to elicit a systemic biological effect would need to be greater than is possible by dietary consumption( Reference Petrick, Brower-Toland and Jackson 167 ). Additional studies, perhaps utilising larger sample sizes and longer-term administration, and additional scrutiny of the methodologies employed, are needed to address the current discrepancies in the available data. It is yet to be definitively established whether or not exogenous miRNA can be taken up in sufficient levels to have consequences for gene expression in real-life situations. However, if this were possible, it would have significant implications for the analysis of potential dietary modulation of miRNA profiles, as past studies may have inadvertently identified exogenous miRNA as endogenous miRNA.

Conclusion

Investigation of the role of nutrition and diet in the modulation of miRNA profiles remains a relatively new field of investigation. Several observational studies and model systems have identified potential and logical links between nutritional status, miRNA profile and disease status; however, these links are, as yet, far from conclusive. In particular, additional studies in human cohorts are required.

Furthermore, the implications of identified associations cannot be fully appreciated without additional research to identify the mRNA targets of more miRNA, as the majority remain poorly defined. Additional functional studies are required in future research to understand if there are physiological consequences for modulation of miRNA by micronutrients and if these relationships can be harnessed for therapeutic or diagnostic purposes. The increasing affordability and practicality of miRNA assays are likely to contribute to an increased volume of investigation in coming years.

The proposal that plant miRNA can reach human circulation introduces an additional area for consideration, as, if proven, this may confound the interpretation of responses that are attributed to endogenous nutrition-related miRNA and may, in fact, contribute to pathophysiology. The identified roles for nutritional and dietary components suggest that dietary influences should be considered in future cohort studies attempting to link miRNA expression profiles with disease states. Micronutrients also offer a potential novel avenue for the development of therapeutic supplements that target miRNA modulation.

Supplementary material

To view supplementary material for this article, please visit http://dx.doi.org/10.1017/S0954422414000043

Acknowledgements

The present review was not funded by any granting body.

E. L. B. wrote the manuscript and was involved in its conceptualisation; Z. Y, M. V., K. D. and M. L. oversaw conceptualisation and implementation of the manuscript. All authors reviewed and approved the manuscript.

The authors do not have any conflict of interest.

References

1 Papageorgiou, N, Tousoulis, D, Androulakis, E, et al. (2012) The role of microRNAs in cardiovascular disease. Curr Med Chem 19, 26052610.CrossRefGoogle ScholarPubMed
2 Lorenzen, J, Kumarswamy, R, Dangwal, S, et al. (2012) MicroRNAs in diabetes and diabetes-associated complications. RNA Biol 9, 820827.Google Scholar
3 Calin, G & Croce, C (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6, 857866.Google Scholar
4 Lee, R, Feinbaum, R & Ambros, V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 . Cell 75, 843854.Google Scholar
5 Ruvkun, G (2001) Glimpses of a tiny RNA world. Molecular Biology 294, 797799.Google Scholar
6 Selbach, M, Schwanhausser, B, Thierfelder, T, et al. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455, 6471.Google Scholar
7 Brennecke, J, Stark, A, Russell, R, et al. (2005) Principles of microRNA-target recognition. PLoS Biol 3, e85.Google Scholar
8 Friedman, R, Farh, K, Burge, C, et al. (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19, 92105.Google Scholar
9 Ariel, D & Upadhyay, D (2012) The role and regulation of microRNAs in asthma. Curr Opin Allergy Clin Immunol 12, 4952.Google Scholar
10 Wang, H, Peng, W, Ouyang, X, et al. (2012) Circulating microRNAs as candidate biomarkers in patients with systemic lupus erythematosus. Transl Res 160, 198206.Google Scholar
11 Weiland, M, Gao, X, Zhou, L, et al. (2012) Small RNAs have a large impact: circulating microRNAs as biomarkers for human diseases. RNA Biol 9, 850859.Google Scholar
12 Gilad, S, Meiri, E, Yogev, Y, et al. (2008) Serum microRNAs are promising novel biomarkers. PLoS ONE 3, e3148.Google Scholar
13 Bartel, D (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281297.Google Scholar
14 Patil, V, Zhou, R & Rana, T (2014) Gene regulation by non-coding RNAs. Crit Rev Biochem Mol Biol 49, 1632.Google Scholar
15 Yekta, S, Shih, I & Bartel, D (2004) MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594596.Google Scholar
16 Davis, E, Caiment, F, Tordoir, X, et al. (2005) RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus. Curr Biol 15, 743749.Google Scholar
17 Chendrimada, T, Finn, K, Ji, X, et al. (2007) MicroRNA silencing through RISC recruitment of eIF6. Nature 447, 823828.Google Scholar
18 Petersen, C, Bordeleau, M, Pelletier, J, et al. (2006) Short RNAs repress translation after initiation in mammalian cells. Mol Cell 21, 533542.Google Scholar
19 Wu, L, Fan, J & Belasco, J (2006) MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A 103, 40344039.Google Scholar
20 Vasudevan, S, Tong, Y & Steitz, J (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 19311934.Google Scholar
21 Orom, U, Nielsen, F & Lund, A (2008) MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Cell 30, 460471.Google Scholar
22 Place, R, Li, L, Pookot, D, et al. (2008) MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A 105, 16081613.Google Scholar
23 Vasudevan, S (2012) Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA 3, 311330.Google Scholar
24 Weichenhan, D & Plass, C (2013) The evolving epigenome. Hum Mol Genet 22, R1R6.Google Scholar
25 Chuang, J & Jones, P (2007) Epigenetics and microRNAs. Pediatr Res 61, 24R29R.Google Scholar
26 Saetrom, P, Snøve, OJ & Rossi, J (2007) Epigenetics and microRNAs. Pediatr Res 61, 17R23R.Google Scholar
27 Sato, F, Tsuchiya, S, Meltzer, S, et al. (2011) MicroRNAs and epigenetics. FEBS J 278, 15981609.Google Scholar
28 Berger, S, Kouzarides, T, Shiekhattar, R, et al. (2009) An operational definition of epigenetics. Genes Dev 23, 781783.Google Scholar
29 Park, L, Friso, S & Choi, S (2012) Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 71, 7583.Google Scholar
30 Jaenisch, R & Bird, A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33, 245254.Google Scholar
31 Deaton, A & Bird, A (2011) CpG islands and the regulation of transcription. Genes Dev 25, 10101022.CrossRefGoogle ScholarPubMed
32 Das, C & Tyler, J (2012) Histone exchange and histone modifications during transcription and aging. Biochim Biophys Acta 1819, 332342.CrossRefGoogle Scholar
33 Costello, J, Krzywinski, M & Marra, M (2009) A first look at entire human methylomes. Nat Biotechnol 27, 11301132.Google Scholar
34 Christensen, B, Houseman, E, Marsit, C, et al. (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5, e1000602.CrossRefGoogle ScholarPubMed
35 Fabbri, M & Calin, G (2010) Epigenetics and miRNAs in human cancer. Adv Genet 70, 8799.Google Scholar
36 Martello, G, Rosato, A, Ferrari, F, et al. (2010) A microRNA targeting dicer for metastasis control. Cell 141, 11951207.Google Scholar
37 Lujambio, A, Calin, G, Villanueva, A, et al. (2008) A microRNA DNA methylation signature for human metastasis. Proc Natl Acad Sci U S A 105, 1355613561.Google Scholar
38 Lujambio, A & Esteller, M (2009) How epigenetics can explain human metastisis: a new role for microRNAs. Cell Cycle 8, 377382.Google Scholar
39 Saito, Y, Liang, G, Egger, G, et al. (2006) Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin modifiying drugs in human cancer cells. Cancer Cell 9, 435443.Google Scholar
40 Guan, P, Yin, Z, Li, X, et al. (2012) Meta-analysis of human lung cancer microRNA expression profiling studies comparing cancer tissues with normal tissues. J Exp Clin Cancer Res 31, 54.Google Scholar
41 Lehmann, U, Hasemeier, B, Christgen, M, et al. (2008) Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol 214, 1724.Google Scholar
42 Datta, J, Kutay, H, Nasser, M, et al. (2008) Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68, 50495058.Google Scholar
43 Nebbioso, A, Carafa, V, Benedetti, R, et al. (2012) Trials with ‘epigenetic’ drugs: an update. Mol Oncol 6, 657682.Google Scholar
44 Nasser, M, Datta, J, Nuovo, G, et al. (2008) Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apotosis by miR-1. J Biol Chem 283, 3339433405.Google Scholar
45 Scott, G, Mattie, M, Berger, C, et al. (2006) Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 66, 12771281.Google Scholar
46 Wada, T, Kikuchi, J & Furukawa, Y (2012) Histone deacetylase 1 enhances microRNA processing via deacetylation of DGCR8. EMBO Rep 13, 142149.Google Scholar
47 Fabbri, M, Garzon, R, Cimmino, A, et al. (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferase 3A and 3B. Proc Natl Acad Sci U S A 104, 1580515810.Google Scholar
48 Garzon, R, Liu, S, Fabbri, M, et al. (2009) MicroRNA-29b induces global DNA hypomethylation and tumour suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectlty DNMT1. Blood 113, 64116418.Google Scholar
49 Zhao, S, Wang, Y, Liang, Y, et al. (2011) MicroRNA-126 regulates DNA methylation in CD4+T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum 63, 13761386.Google Scholar
50 Pan, W, Zhu, S, Yuan, M, et al. (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 184, 67736781.Google Scholar
51 Duursma, A, Kedde, M, Schrier, M, et al. (2008) miR-148 targets human DNMR3b protein coding region. RNA Biol 14, 872877.Google Scholar
52 Sander, S, Bullinger, L, Klapproth, K, et al. (2008) MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 112, 42024212.Google Scholar
53 Varambally, S, Cao, Q, Mani, R, et al. (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 16951699.Google Scholar
54 Friedman, J, Liang, G, Liu, C, et al. (2009) The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res 69, 26232629.Google Scholar
55 Gandellini, P, Folini, M, Longoni, N, et al. (2009) miR-205 exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cε. Cancer Res 69, 22872295.Google Scholar
56 Juan, A, Kumar, R, Marx, J, et al. (2009) miR-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells. Mol Cell 36, 6174.Google Scholar
57 Fan, D, Tsang, F, Tam, A, et al. (2013) Histone lysine methyltransferase, SUV39H1, promotes HCC progression and is negatively regulated by microRNA-125b. Hepatology 57, 637647.Google Scholar
58 Sluijter, J, van Mil, A, van Vliet, P, et al. (2010) MicroRNA-1 and -499 regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells. Arterioscler Thromb Vasc Biol 30, 859868.Google Scholar
59 Zhao, Y, Ransom, J, Li, A, et al. (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129, 303317.Google Scholar
60 Chen, J-F, Mandel, E, Thomson, J, et al. (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38, 228233.Google Scholar
61 Song, B, Wang, Y, Xi, Y, et al. (2009) Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene 28, 40654074.Google Scholar
62 Noonan, E, Place, R, Pookot, D, et al. (2009) miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 28, 17171724.Google Scholar
63 Buurman, R, Gürlevik, E, Schäffer, V, et al. (2012) Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 143, 811820e15.Google Scholar
64 Roccaro, A, Sacco, A, Jia, X, et al. (2010) MicroRNA-dependent modulation of histone acetylation in Waldenstrom macroglobulinemia. Blood 116, 15061514.Google Scholar
65 Barker, D (1995) Fetal origins of coronary heart disease. BMJ 311, 171174.Google Scholar
66 Barker, D (1995) Intrauterine programming of adult disease. Mol Med Today 1, 418423.Google Scholar
67 Barker, D, Winter, P, Osmond, C, et al. (1989) Weight in infancy and death from ischaemic heart disease. Lancet ii, 577580.Google Scholar
68 Canani, R, Costanzo, M, Leone, L, et al. (2011) Epigenetic mechanisms elicited by nutrition in early life. Nutr Res Rev 24, 198205.Google Scholar
69 Tobi, E, Slagboom, P, van Dongen, J, et al. (2012) Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19. PLOS ONE 7, e37933.Google Scholar
70 Lumey, L, Terry, M, Delgado-Cruzata, L, et al. (2012) Adult global DNA methylation in relation to pre-natal nutrition. Int J Epidemiol 41, 116123.Google Scholar
71 Heijmans, B, Tobi, E, Stein, A, et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105, 1704617049.Google Scholar
72 Fraga, M, Ballestar, E, Paz, M, et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102, 1060410609.Google Scholar
73 Mill, J, Dempster, E, Caspi, A, et al. (2006) Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene. Am J Med Genet B Neuropsychiatr Genet 141B, 421425.Google Scholar
74 Talens, R, Christensen, K, Putter, H, et al. (2012) Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell 11, 694703.Google Scholar
75 Zhao, J, Goldberg, J & Vaccarino, V (2013) Promoter methylation of serotonin transporter gene is associated with obesity measures: a monozygotic twin study. Int J Obes (Lond) 37, 140145.Google Scholar
76 Roberts, C & Barnard, R (2005) Effects of exercise and diet on chronic disease. J Appl Physiol 98, 330.Google Scholar
77 World Health Organization (2003) Diet, Nutrition and the Prevention of Chronic Diseases. Joint WHO/FAO Expert Consultation. WHO Technical Report Series no. 916 . Geneva: WHO.Google Scholar
78 Teunissen, S, Wesker, W, Kruitwagen, C, et al. (2007) Symptom prevalance in patients with incurable cancer: a systematic review. J Pain Symptom Manage 34, 94104.Google Scholar
79 Witwer, K (2012) Xenomirs and miRNA homeostasis in health and disease. RNA Biol 9, 11471154.Google Scholar
80 Lundstrom, K (2012) MicroRNA and diet in disease prevention and treatment. J Med Res Sci 2, 1118.Google Scholar
81 McKay, J & Mathers, J (2011) Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf) 202, 103118.Google Scholar
82 Pittas, A, Lau, J, Hu, F, et al. (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92, 20172029.Google Scholar
83 Wang, T, Pencina, M, Booth, S, et al. (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117, 503511.Google Scholar
84 Adorini, L (2008) Penna G Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 4, 404412.Google Scholar
85 Lappe, J, Travers-Gustafson, D, Davies, K, et al. (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85, 15861591.Google Scholar
86 Lamprecht, S & Lipkin, M (2003) Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3, 601614.Google Scholar
87 Carlberg, C (2003) Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res 164, 2942.Google Scholar
88 Sonkoly, E, Lovén, J, Xu, N, et al. (2012) MicroRNA-203 functions as a tumor suppressor in basal cell carcinoma. Oncogenesis 1, e3.Google Scholar
89 Giangreco, A, Vaishnav, A, Wagner, D, et al. (2013) Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue. Cancer Prev Res (Phila) 6, 483494.Google Scholar
90 Essa, S, Reichrath, S, Mahlknecht, U, et al. (2012) Signature of VDR miRNAs and epigenetic modulation of vitamin D signaling in melanoma cell lines. Anticancer Res 32, 383389.Google Scholar
91 Essa, S, Denzer, N, Mahlknecht, U, et al. (2010) VDR microRNA expression and epigenetic silencing of vitamin D signaling in melanoma cells. J Steroid Biochem Mol Biol 121, 110113.Google Scholar
92 Alvarez-Díaz, S, Valle, N, Ferrer-Mayorga, G, et al. (2012) MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum Mol Genet 21, 21572165.Google Scholar
93 Mohri, T, Nakajima, M, Takagi, S, et al. (2009) MicroRNA regulates human vitamin D receptor. Int J Cancer 125, 13281333.Google Scholar
94 Zhang, J, Yang, Y, Yang, T, et al. (2010) MicroRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 103, 12151220.Google Scholar
95 Lee, J, Jeong, W, Lim, W, et al. (2013) Hypermethylation and post-transcriptional regulation of DNA methyltransferases in the ovarian carcinomas of the laying hen. PLOS ONE 8, e61658.Google Scholar
96 Padi, S, Zhang, Q, Rustum, Y, et al. (2013) MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology 145, 437446.Google Scholar
97 Ting, H, Messing, J, Yasmin-Karim, S, et al. (2013) Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D. J Biol Chem 288, 19.Google Scholar
98 Guan, H, Liu, C, Chen, Z, et al. (2013) 1,25-Dihydroxyvitamin D3 up-regulates expression of hsa-let-7a-2 through the interaction of VDR/VDRE in human lung cancer A549 cells. Gene 522, 142146.Google Scholar
99 Wang, X, Gocek, E, Liu, C, et al. (2009) MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3 . Cell Cycle 8, 736741.Google Scholar
100 Peng, X, Vaishnav, A, Murillo, G, et al. (2010) Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells. J Cell Biochem 110, 13241333.Google Scholar
101 Fulda, S, Gorman, A, Hori, O, et al. (2010) Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010, 214074.Google Scholar
102 Jia, Y, Cong, R, Li, R, et al. (2012) Maternal low-protein diet induces gender-dependent changes in epigenetic regulation of the glucose-6-phosphatase gene in newborn piglet liver. J Nutr 142, 16591665.Google Scholar
103 Jorde, R, Svartberg, J, Joakimsen, R, et al. (2012) Plasma profile of microRNA after supplementation with high doses of vitamin D3 for 12 months. BMC Res Notes 5, 245.Google Scholar
104 Enquobahrie, D, Williams, M, Qiu, C, et al. (2011) Global maternal early pregnancy peripheral blood mRNA and miRNA expression profiles according to plasma 25-hydroxyvitamin D concentrations. J Matern Fetal Neonatal Med 24, 10021012.Google Scholar
105 Nowson, C, McGrath, J, Ebeling, P, et al. (2012) Vitamin D and health in adults in Australia and New Zealand: a position statement. Med J Aust 196, 686687.Google Scholar
106 Lucock, M (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 71, 121138.Google Scholar
107 Lucock, M & Daskalakis, I (2000) New perspectives on folate status: a differential role for the vitamin in cardiovascular disease, birth defects and other conditions. Br J Biomed Sci 57, 254260.Google Scholar
108 Lianga, Y, Lib, Y, Liub, Z, et al. (2012) Mechanism of folate deficiency-induced apoptosis in mouse embryonic stem cells: cell cycle arrest/apoptosis in G1/G0 mediated by microRNA-302a and tumor suppressor gene Lats2. Int J Biochem Cell Biol 44, 17501760.Google Scholar
109 Marsit, C, Eddy, K & Kelsey, K (2006) MicroRNA responses to cellullar stress. Cancer Res 66, 1084310848.Google Scholar
110 Tryndyak, V, Ross, S, Beland, F, et al. (2009) Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol Carcinog 48, 479487.Google Scholar
111 Pogribny, I, Ross, S, Wise, C, et al. (2006) Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency. Mutat Res 593, 8087.Google Scholar
112 Kutay, H, Bai, S, et al. (2006) Datta J,./i} Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 99, 671678.Google Scholar
113 Pogribny, I, Tryndyak, V, Ross, S, et al. (2008) Differential expression of microRNAs during hepatocarcinogenesis induced by methyl deficiency in rats. Nutr Rev 66, Suppl. 1, S33S35.Google Scholar
114 Wang, B, Majumder, S, Nuovo, G, et al. (2009) Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL6 mice. Hepatology 50, 11521161.Google Scholar
115 Duester, G (2008) Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921931.Google Scholar
116 Kawasaki, H & Taira, K (2003) Functional analysis of microRNAs during retinoic acid-induced neuronal differentiation of human NT2 cells. Nucleic Acid Res Suppl 26, 243244.Google Scholar
117 Annibali, D, Gioia, U, Savino, M, et al. (2012) A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2. PLOS ONE 7, e40269.Google Scholar
118 Das, S, Foley, N, Bryan, K, et al. (2010) MicroRNA mediates DNA demethylation events triggered by retinoic acid during neuroblastoma cell differentiation. Cancer Res 70, 78747881.Google Scholar
119 Beveridge, N, Tooney, P, Carroll, A, et al. (2009) Down-regulation of miR-17 family expression in response to retinoic acid induced neuronal differentiation. Cell Signal 21, 18371845.Google Scholar
120 Zhao, J, Sun, D, Wang, J, et al. (2008) Retinoic acid downregulates microRNAs to induce abnormal development of spinal cord in spina bifida rat model. Childs Nerv Syst 24, 495–492.Google Scholar
121 Cloonan, N, Brown, M, Steptoe, A, et al. (2008) The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 9, R127.Google Scholar
122 Yang, F, Yin, Y, Wang, F, et al. (2010) miR-17-5p promotes migration of human hepatocellular carcinoma cells through the p38 mitogen-activated protein kinase-heat shock protein 27 pathway. Hepatology 51, 16141623.Google Scholar
123 Wang, X, Gong, JN, Yu, J, et al. (2012) MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. Blood 119, 49925004.Google Scholar
124 Jian, P, Li, Z, Fang, T, et al. (2011) Retinoic acid induces HL-60 cell differentiation via the upregulation of miR-663. J Hematol Oncol 4, 20.Google Scholar
125 Garzon, R, Pichiorri, F, Palumbo, T, et al. (2007) MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 26, 41484157.CrossRefGoogle ScholarPubMed
126 Rossi, A, D'Urso, O, Gatto, G, et al. (2010) Non-coding RNAs change their expression profile after retinoid induced differentiation of the promyelocytic cell line NB4. BMC Res Notes 3, 24.Google Scholar
127 Juraschek, S, Guallar, E, Appel, L, et al. (2012) Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials. Am J Clin Nutr 95, 10791088.Google Scholar
128 Da Costa, L, Badawi, A & El-Sohemy, A (2012) Nutrigenetics and modulation of oxidative stress. Ann Nutr Metab 60, Suppl. 3, 2736.Google Scholar
129 Riccioni, G, Frigiola, A, Pasquale, S, et al. (2012) Vitamin C and E consumption and coronary heart disease in men. Front Biosci (Elite Ed) 4, 373380.Google Scholar
130 Hung, P, Chen, F, Kuang, S, et al. (2010) miR-146a induces differentiation of periodontal ligament cells. J Dent Res 89, 252257.Google Scholar
131 Kim, Y, Ku, S, Rosenwaks, Z, et al. (2010) MicroRNA expression profiles are altered by gonadotropins and vitamin C status during in vitro follicular growth. Reprod Sci 17, 10811089.Google Scholar
132 Woodson, K, Tangrea, J, Barrett, M, et al. (1999) Serum α-tocopherol and subsequent risk of lung cancer among male smokers. J Natl Cancer Inst 91, 17381743.Google Scholar
133 Huang, H, Alberg, A, Norkus, E, et al. (2003) Prospective study of antioxidant micronutrients in the blood and the risk of developing prostate cancer. Am J Epidemiol 157, 335344.Google Scholar
134 Gridley, G, McLaughlin, J, Block, G, et al. (1992) Vitamin supplement use and reduced risk of oral and pharyngeal cancer. Am J Epidemiol 135, 10831092.Google Scholar
135 Longnecker, M, Martin-Moreno, J, Knekt, P, et al. (1992) Serum α-tocopherol concentration in relation to subsequent colorectal cancer: pooled data from five cohorts. J Natl Cancer Inst 84, 430435.CrossRefGoogle ScholarPubMed
136 Banim, P, Luben, R, McTaggart, A, et al. (2013) Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers. Gut 62, 14891496.CrossRefGoogle ScholarPubMed
137 Zhang, W, Shu, X, Li, H, et al. (2012) Vitamin intake and liver cancer risk: a report from two cohort studies in China. J Natl Cancer Inst 104, 11731181.Google Scholar
138 Ocké, M, Bueno-de-Mesquita, H, Feskens, E, et al. (1997) Repeated measurements of vegetables, fruits, β-carotene, and vitamins C and E in relation to lung cancer. The Zutphen Study. Am J Epidemiol 145, 358365.Google Scholar
139 Gilbert, R, Metcalfe, C, Fraser, W, et al. (2012) Associations of circulating retinol, vitamin E, and 1,25-dihydroxyvitamin D with prostate cancer diagnosis, stage, and grade. Cancer Causes Control 23, 18651873.Google Scholar
140 Lonn, E, Bosch, J, Yusuf, S, et al. (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293, 13381347.Google Scholar
141 Miller, E, Pastor-Barriuso, R, Dalal, D, et al. (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142, 3746.Google Scholar
142 Rimbach, G, Moehring, J, Huebbe, P, et al. (2010) Gene-regulatory activity of α-tocopherol. Molecules 15, 17461761.Google Scholar
143 Esau, C, Davis, S, Murray, S, et al. (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3, 8798.Google Scholar
144 Elmén, J, Lindow, M, Silahtaroglu, A, et al. (2008) Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res 36, 11531162.Google Scholar
145 Rayman, M (2012) Selenium and human health. Lancet 379, 12561268.Google Scholar
146 Rayman, M, Blundell-Pound, G, Pastor-Barriuso, R, et al. (2012) A randomized trial of selenium supplementation and risk of type-2 diabetes, as assessed by plasma adiponectin. PLOS ONE 7, e45269.Google Scholar
147 Bleys, J, Navas-Acien, A & Guallar, E (2007) Serum selenium and diabetes in U.S. adults. Diabetes Care 30, 829834.Google Scholar
148 Laclaustra, M, Navas-Acien, A, Stranges, S, et al. (2009) Serum selenium concentrations and diabetes in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2003-2004. Environ Health Perspect 117, 14091413.Google Scholar
149 Sarveswaran, S, Liroff, J, Zhou, Z, et al. (2010) Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: implication for the treatment of early-stage prostate cancer. Int J Oncol 36, 14191428.Google Scholar
150 Hermeking, H (2007) p53 enters the microRNA world. Cancer Cell 12, 414418.Google Scholar
151 Prasad, A (2012) Discovery of human zinc deficiency: 50 years later. J Trace Elem Med Biol 26, 6669.CrossRefGoogle ScholarPubMed
152 Ryu, M, Langkamp-Henken, B, Chang, S, et al. (2011) Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis. Proc Natl Acad Sci U S A 108, 2097020975.Google Scholar
153 Pogue, A, Percy, M, Cui, J, et al. (2011) Up-regulation of NF-κB-sensitive miRNA-125b and miRNA-146a in metal sulfate-stressed human astroglial (HAG) primary cell cultures. J Inorg Biochem 105, 14341437.Google Scholar
154 Barr, I, Smith, A, Chen, Y, et al. (2012) Ferric, not ferrous, heme activates RNA-binding protein DGCR8 for primary microRNA processing. Proc Natl Acad Sci U S A 109, 19191924.Google Scholar
155 Ma, Z, Xue, Z, Zhang, H, et al. (2012) Local and global effects of Mg2+ on Ago and miRNA-target interactions. J Mol Model 18, 37693781.Google Scholar
156 Zhang, L, Hou, D, Chen, X, et al. (2012) Exogenous plant miR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res 22, 107126.Google Scholar
157 Newmark, P, Reddien, P, Cebrià, F, et al. (2003) Ingestion of bacterially expressed double-stranded RNA inhibits gene expression in planarians. Proc Natl Acad Sci U S A 100, Suppl. 1, 1186111865.Google Scholar
158 Terenius, O, Papanicolaou, A, Garbutt, J, et al. (2011) RNA interference in Lepidoptera: an overview of successful and unsuccessful studies and implications for experimental design. J Insect Physiol 57, 231245.Google Scholar
159 Omarov, R & Scholthof, H (2012) Biological chemistry of virus-encoded suppressors of RNA silencing: an overview. Methods Mol Biol 894, 3956.Google Scholar
160 Zhou, Q, Li, M, Wang, X, et al. (2012) Immune-related microRNAs are abundant in breast milk exosomes. Int J Biol Sci 8, 118123.Google Scholar
161 Izumi, H, Kosaka, N, Shimizu, T, et al. (2012) Bovine milk contains microRNA and messenger RNA that are stable under degradative conditions. J Dairy Sci 95, 48314841.Google Scholar
162 Kosaka, N, Izumi, H, Sekine, K, et al. (2010) MicroRNA as a new immune-regulatory agent in breast milk. Silence 1, 7.Google Scholar
163 Jiang, M, Sang, X & Hong, Z (2012) Beyond nutrients: food-derived microRNAs provide cross-kingdom regulation. Bioessays 34, 280284.Google Scholar
164 Witwer, K, McAlexander, M, Queen, S, et al. (2013) Real-time quantitative PCR and droplet digital PCR for plant miRNAs in mammalian blood provide little evidence for general uptake of dietary miRNAs: limited evidence for general uptake of dietary plant xenomiRs. RNA Biol 10, 10801086.Google Scholar
165 Snow, J, Hale, A, Isaacs, S, et al. (2013) Ineffective delivery of diet-derived microRNAs to recipient animal organisms. RNA Biol 10, 11071116.Google Scholar
166 Zhang, Y, Wiggins, B, Lawrence, C, et al. (2012) Analysis of plant-derived miRNAs in animal small RNA datasets. BMC Genomics 13, 381.CrossRefGoogle ScholarPubMed
167 Petrick, J, Brower-Toland, B, Jackson, A, et al. (2013) Safety assessment of food and feed from biotechnology-derived crops employing RNA-mediated gene regulation to achieve desired traits: a scientific review. Regul Toxicol Pharmacol 66, 167186.Google Scholar
Figure 0

Fig. 1 MicroRNA (miRNA) mechanisms of action. miRNA can act by (a) blocking gene transcription or (b) inducing miRNA instability or degradation. mRNA, messenger RNA; RISC, RNA-induced silencing complex.

Figure 1

Fig. 2 Summary of the potential effects of vitamins and minerals on gene expression. MicroRNA (miRNA) are intrinsically involved in gene regulation. Vitamins and minerals can induce the expression of miRNA via the activation of transcription factors/response elements, leading to altered gene expression by the induction of messenger RNA (mRNA) degradation or the repression of translation. Vitamins and minerals may also alter the function of the classical epigenetic machinery, altering expression of DNA methyltransferases (DNMT) and histone modification enzymes, such as histone deacetylases and histone acetyltransferases. Modulation of these enzymes leads to changes in DNA methylation status and histone modifications, which in turn can modulate the expression of other genes, including miRNA themselves. These interconnecting pathways allow for the modulation of complex processes and feedback loops.

Figure 2

Table 1 Epigenetic microRNA with identified vitamin or mineral regulators

Supplementary material: File

Beckett supplementary material

Beckett supplementary material

Download Beckett supplementary material(File)
File 193.5 KB