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. Author manuscript; available in PMC: 2016 Jul 1.
Published in final edited form as: Arterioscler Thromb Vasc Biol. 2015 Jun 4;35(7):1557–1561. doi: 10.1161/ATVBAHA.115.305041

Chromatin modifications associated with diabetes and obesity

Dustin E Schones 1, Amy Leung 1, Rama Natarajan 1
PMCID: PMC4482788  NIHMSID: NIHMS694884  PMID: 26044585

Abstract

The incidence of obesity across the globe has doubled over the last several decades, leading to escalating rates of diabetes, cardiovascular disease and other complications. Given this dramatic rise in disease incidence, understanding the etiology of these diseases is therefore of paramount importance. Metabolic diseases such as obesity and diabetes result from a multitude of genetic and environmental factors. While the genetic basis of these diseases has been extensively studied, the molecular pathways whereby environmental factors influence disease progression are only beginning to be understood. One manner by which environmental factors can contribute to disease progression is through modifications to chromatin. The highly structured packaging of the genome into the nucleus through chromatin has been shown to be fundamental to tissue-specific gene regulation. Modifications to chromatin can regulate gene expression and are involved in a myriad of biological functions, and hence disruption of these modifications is central to many human diseases. These modifications can furthermore be epigenetic in nature, thereby contributing to prolonged disease risk. Recent work has demonstrated that modifications to chromatin are associated with the progression of both diabetes and obesity, which is the subject of this review.

Keywords: chromatin, epigenetics, gene by environment, diabetes, obesity

Introduction

The human genome is packaged into the nucleus by wrapping DNA around collections of histone proteins to form nucleosomes in chromatin. The chromatin structure is subject to many different types of modifications, including DNA methylation, ATP-dependent chromatin remodeling, histone post-translational modification (PTM), histone variant incorporation and interaction with non-coding RNAs (Figure 1). Modifications to chromatin accompany many important biological functions, including cell differentiation and transcription.1, 2 Aberrant modifications are associated with many human diseases, including diabetes, obesity, cardiovascular disease and many types of cancer.3 Importantly, these chromatin modifications are cell-type-specific and can be mitotically heritable, or epigenetic in nature, thereby contributing to long-term gene expression changes.4

Figure 1. Chromatin modifications demonstrated to be associated with diabetes and obesity.

Figure 1

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DNA methylation,24, 26 ATP-dependent remodeling,21 histone post-translational modifications (PTM)28–31, 34 and non-coding RNAs (ncRNAs) 35, 40 have been demonstrated to be altered in diabetes and obesity.

Much has been written regarding the impact of perinatal exposure to environmental factors on epigenetic modifications, transgenerational inheritance and phenotype of offspring.5–7 This Brief Review will instead focus on recent work describing modifications to chromatin that are associated with type 2 diabetes (T2D) and obesity that are influenced by nutrients and excess consumption of calories from fats and refined carbohydrates.8 We also discuss the role of epigenetics in the vascular complications that are significantly accelerated in diabetes and obesity. Furthermore, we highlight the emerging evidence of gene and environmental interaction in these diseases.

Nutritional factors and chromatin modifications

Nutritional factors such as micronutrients from diet can impact chromatin modifications by directly providing substrates necessary for modification or by providing co-factors that modulate the enzymatic activities of chromatin modifying enzymes. For example, S-adenosylmethionine (SAM), a universal methyl-donor for methyltransferases,9 is synthesized in the methionine cycle from precursors in the diet of an individual. Lack of methyl donors from diet can result in DNA hypomethylation in rodent liver10 and brain11, and similar effects are supposed in humans. A recent and extensive review12 described many studies of the impact of micronutrients on chromatin modifications. Here we instead review some of the seminal work exploring the impact that diet can have on chromatin modifications and focus on more recent work.

The agouti viable yellow mouse (Avy) is a classic mouse model for studying fetal programming. The Avy allele contains an intracisternal A particle (IAP) retrotransposon upstream of the Agouti gene which can be DNA methylated. Interestingly, genetically identical offspring vary in agouti expression depending on developmental availability of methyl donors in the diet13 which influences the DNA methylation state of the IAP retrotransposon upstream of the Agouti gene.14 While the Agouti gene encodes a signaling protein that promotes yellow pigmentation, it is also antagonistic to melanocortin receptors, a regulator of feeding behavior and metabolism.15 Differential methylation of the IAP upstream of the Agouti gene therefore results in offspring with varying coat colors as well as differential susceptibility to diabetes, obesity and cancer.16

Chromatin modifications associated with obesity

In addition to the effects of nutrients on chromatin modifications, diet is also a key factor driving metabolic disease. Excess consumption of calories from fats and refined carbohydrates are associated with the development of obesity, non-alcoholic fatty liver, T2D and other metabolic diseases.8 Diet-induced obesity is also associated with modifications to chromatin in the brain,17 though the molecular mechanisms underlying these chromatin modifications are less clear. Primary hepatocytes treated with palmitate and oleate mimicking high fat diet express histone demethylase genes at elevated levels.18 Furthermore, human pancreatic islets treated with palmitate have altered DNA methylation patterns that are associated with gene expression changes for 290 genes, with numerous pathways altered, including insulin signaling and other metabolic pathways.19

Rats developing obesity from high fat diet show altered histone modifications at p16 and p21 loci.20 More recently, it has been shown that C57BL/6J mice fed a high fat diet to induce obesity display chromatin remodeling in liver tissue across the genome.21 Furthermore, the greatest degree of remodeling was at regulatory regions bound by transcription factors (TFs) such as HNF4α, CEBP/α and FOXA1, and marked by histone lysine-4 monomethylation (H3K4me1), a chromatin modification associated with regulatory regions (Figure 2).21 A large number regions displaying chromatin remodeling occurred near genes associated with metabolism and insulin signaling. Intriguingly, DBA/2J mice fed a high fat diet for the same time period also displayed chromatin remodeling in the liver, but the regions of greatest remodeling were largely unique to the DBA/2J genome, further revealing a link between genetic and environmental factor in diet-induced obesity.21 Interestingly, studies with the Hybrid Mouse Diversity Panel have demonstrated tremendous strain specific diversity in metabolic responses to high fat diet in mice,22, 23 further underscoring the genetic-epigenetic cross-talk and a possible correlation in humans.

Figure 2. Diet-induced obesity chromatin remodelling.

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Diet-induced obesity leads to chromatin remodeling in the liver at regulatory regions across the genome. These regions are pre-marked by H3K4me1 and bound by liver TFs (see text for details) and can lead to the expression of metabolic pathway genes such as Lpin1.

Chromatin modifications and diabetes

It was recently demonstrated that DNA methylation changes can be induced in adipocytes of mice on a HF diet.24 It was further shown that homologous loci in the human genome displayed differential methylation pre- and post gastric bypass, demonstrating cross-species conservation of differential methylation induced by HF diet.24 These regions of differential methylation overlapped with T2D risk loci that, for the most part, were deemed not significant by genomewide association analysis alone. However, it was shown that four of these genes are involved in insulin resistance, indicating that further integration of epigenetic data with genetic studies can be utilized to identify molecular pathways of disease.24

An additional study evaluating monozygotic twin pairs concordant or discordant for T2D also revealed differentially methylated regions (DMRs) in peripheral blood that overlap with GWAS loci associated with T2D.25 Interestingly, pancreatic islet cells also display variation in DNA methylation across different individuals.26 These variable methylation regions are associated not only with gene expression variation in islets but also with secretion of insulin, indicating that DNA methylation may be an important mediator in the development of diabetes.26 DNA methylation may also be a key player in the development of diabetic vascular complications, perhaps as a result of the hyperglycemic state.27, 28

In addition to DNA methylation, post-translational modifications to histone proteins are also involved in the development of diabetes and its vascular complications.28 Differences in the levels of histone PTMs such as H3K9 acetylation (H3K9ac) and H3K4 methylation (H3K4me) (chromatin marks associated with expressed genes) at key fibrotic, inflammatory and cell cycle genes are observed in renal mesangial cells treated with Transforming growth factor-beta 1 (TGF-?1) or high glucose.29, 30 PTM changes were also noted in renal glomeruli of diabetic mice compared to glomeruli from non-diabetic control mice.31 These chromatin modifications observed in the kidney can contribute to diabetic nephropathy, while similar chromatin modifications in distinct target organs can contribute to other diabetic micro- and macro-vascular complications such as retinopathy and atherosclerosis.27, 28, 32 Inflammation and monocyte/macrophage activation are associated with the pathology of diabetic complications such as atherosclerosis and hypertension. Evidence shows that monocytes display changes in key histone lysine modifications at inflammatory genes under diabetic conditions.33 Furthermore, chromatin modifications have been observed in white blood cells from T1D patients compared to normal controls.34 Additional studies have shown changes in post-translational modification to histones occur in vascular smooth muscle cells (VSMCs). With increase in angiotensin II (Ang II), a major contributor to vascular dysfunction which occurs frequently with diabetes and leads to hypertension and atherosclerosis, VSMCs display elevated levels of H3K4me3 and H3K36me3 genome-wide at several pathological genes.35 Interestingly, VSMCs cultured from db/db diabetic mice display sustained decreases in levels of the repressive chromatin mark H3K9me3 at promoters of inflammatory genes compared to control mice, despite being maintained in the same conditions, with reciprocal upregulation of these genes.36 In endothelial cells, transient hyperglycemic conditions resulted in sustained changes in active histone modification in vitro and in vivo at inflammatory genes.37 The data indicate modifications to chromatin occur with disease and may persist after restoration of normoglycemia. They are furthermore potential mediators of ‘metabolic memory’, as discussed below.

Another avenue through which diabetes and its complications can be regulated is through long non-coding RNAs (lncRNAs). These lncRNAs have been shown to be involved in chromatin regulation and gene regulation via epigenetic mechanisms and recent evidence suggests that they may contribute to diabetic complications.38, 39 One study evaluating the potential role of lncRNAs in Ang II signaling identified hundreds of lncRNAs that are expressed in VSMCs, with over a hundred of those being regulated by Ang II. One Ang II-regulated lncRNA, Lnc-Ang362, was characterized to be the host transcript of two miRNAs, miR-222 and miR-221, which are found at the same genomic locus (Figure 3).35 Furthermore, Lnc-Ang362 knockdown revealed that this lncRNA is important for VSMC proliferation. Presumably the proliferative function of Lnc-Ang362 occurs through the actions of miR-221 and miR-222, though it is possible the Lnc-Ang362 also has miRNA-independent effects. Future studies may reveal additional Ang II- and other growth factor regulated lncRNAs that are important for VSMC function and phenotype. These additional lncRNAs may also directly impact chromatin by interacting with chromatin modifying complexes39. LncRNAs can also be induced in macrophages by diabetic conditions in mouse models, affecting the macrophage phenotype and inflammation.40 Finally, lncRNAs have been characterized in islet cells, suggesting a direct role in diabetes development.41

Figure 3. Ang II treatment of VSMCs leads to expression of Lnc-Ang362.

Figure 3

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This lncRNA is a precursor for miR-222 and miR-221. Knockdown of Lnc-Ang362 revealed that this lncRNA is involved in VSMC proliferation.

While studies have implicated DNA methylation, PTMs of histones and lncRNAs in susceptibility and development of diabetes and its complications, a major challenge remaining is to show the direct effect of these chromatin modifications on disease progression. Although obesity and T2D are tightly linked, it was recently demonstrated that disruption of the bromodomain containing 2 protein (Brd2), which plays a role in chromatin remodeling, leads to ‘metabolically healthy’ obesity, without T2D.42 Another recent study demonstrated that a Brd4 inhibitor can inhibit endothelial cell inflammatory genes and also attenuate atherosclerosis development in mouse models.43 These results suggests that chromatin modifications and remodeling are involved in the link between obesity, T2D and other metabolic diseases.

Epigenetics as a mediator of metabolic memory

Clinical studies examining blood glucose control for diabetic patients have demonstrated that complications can continue to develop long after blood glucose normalization, a phenomenon that was originally termed ‘metabolic memory’44, 45. Similarly, many obese people find it difficult to maintain weight loss,46, 47 with long-term physiological changes contributing to weight regain.48, 49 Mice that develop diet-induced obesity (DIO) develop metabolic dysfunctions, including insulin resistance and impaired glucose tolerance, mimicking dysfunctions observed in many obese patients.50, 51 Furthermore, it has been demonstrated that mice transitioning from HF to low fat diet do not completely revert to the same state as mice only maintained on low fat diet.52 Similarly, reports have indicated that the diabetic condition including hyperglycemia can result in persistent histone modification changes in VSMCs and endothelial cells.36, 37 While the molecular mechanisms responsible for this metabolic memory remain unclear, epigenetic mechanisms represent attractive potential mediators.32, 53 A recent epigenomics study with monocytes obtained from patients with T1D that were experiencing metabolic memory of diabetic complications versus those without evidence of metabolic memory supports this concept.54 This study identified significant variation in histone H3K9ac at several inflammatory genes in the patients experiencing metabolic memory and a strong association of H3K9ac with mean hemoglobin A1c levels.54

Links to other diseases

It is now well established that obesity is associated with additional diseases, including cardiovascular disease55 and many types of cancer.56 There is tantalizing evidence that modifications to chromatin might be one manner by which obesity confers susceptibility to the development of other diseases. As an example, obesity is a major risk factor for colorectal cancer, the third most common form of human cancer.57 Recent work profiling histone modifications to predict enhancer utilization in the colon in mouse models of diet-induced obesity and genetic obesity revealed that obesity induces an enhancer profile that more closely resembles colorectal cancer than normal cells.58 Exactly how this happens remains an area of active debate. The chronic inflammation associated with the obesity state is one potential mediator. Indeed, high serum lipid levels are associated with inflammation and other metabolic complications.59

Conclusion

The dramatic increase in obesity, diabetes and related vascular complications is leading to a public health crisis and it is imperative that we act to curb these trends. Fundamental to this will be a greater understanding in the molecular underpinnings of these diseases. Given that these are complex diseases with multiple genetic and environmental influences, the use of integrative methods will be necessary to fully unravel the pathways involved in disease development. These ventures can exploit the rapidly emerging high-throughput sequencing technologies for profiling modifications to chromatin and the associated bioinformatics tools.60 Furthermore, there is much discussion about the use of epigenetic therapies such as those already in use for certain cancers61, although several challenges remain. As described above, much progress has been made in the last several years, but there is still a long way to go.

Acknowledgments

We thank members of the Schones laboratory for helpful discussions and comments.

Sources of Funding

We gratefully acknowledge funding from the National Institute of Health, R01 DK081705, R01 DK058191, R01 HL106089-01 and R01 DK065073 to RN, T32DK007571-24 and NIH-1K01DK104993-01 to AL, and from the Juvenile Diabetes Research Foundation (17-2012-480) to RN.

Nonstandard Abbreviations and Acronyms

PTM

Post-translational modifications

T2D

Type 2 diabetes

T2D

Type 1 diabetes

IAP

intracisternal A particle

TF

Transcription factor

H3K4me1

histone H3 lysine 4 monomethylation

H3K4me3

histone H3 lysine 4 trimethylation

H3K9ac

histone H3 lysine 9 acetylation

TGF-β1

Transforming growth factor-beta 1

VSMC

Vascular smooth muscle cells

Ang II

Angiotensin II

LncRNA

long non-coding RNA

miRNA

microRNAs

Brd2

Bromodomain containing 2 protein

DIO

Diet-induced obesity

Footnotes

Disclosures

None.

References

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