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Functional Implications of DNA Methylation in Adipose Biology

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Functional Implications of DNA Methylation in Adipose Biology Diabetes Volume 68, May 2019 871 Functional Implications of DNA Methylation in Adipose Biology Xiang Ma and Sona Kang Diabetes 2019;68:871–878 | https://doi.org/10.2337/dbi18-0057 The twin epidemics of obesity and type 2 diabetes (T2D) variants have not been tested for causality, and even if are a serious health, social, and economic issue. The proven causal, they cannot fully explain many clinical dysregulation of adipose tissue biology is central to the features such as high heritability, high discordance in adult development of these two metabolic disorders, as adi- monozygotic twins, and the close relationship with envi- pose tissue plays a pivotal role in regulating whole-body ronmental factors (2–5). Therefore, it has long been metabolism and energy homeostasis (1). Accumulating speculated that nongenetic variation, such as epigenetic evidence indicates that multiple aspects of adipose bi- alterations, plays a role in pathogenesis. This notion has PERSPECTIVES IN DIABETES ology are regulated, in part, by epigenetic mechanisms. been borne out by a recent epigenome-wide association The precise and comprehensive understanding of the study that linked alterations in DNA methylation to whole- epigenetic control of adipose tissue biology is crucial to body insulin sensitivity (6). identifying novel therapeutic interventions that target DNA methylation is a reversible epigenetic mark in- epigenetic issues. Here, we review the recent findings volving the covalent transfer of a methyl group to the C-5 on DNA methylation events and machinery in regulating the developmental processes and metabolic function of position of a cytosine residue by DNA methyltransferases adipocytes. We highlight the following points: 1) DNA (DNMTs), usually in the context of a cytosine-guanine methylation is a key epigenetic regulator of adipose dinucleotide (CpG) doublet. Though methylated DNA has development and gene regulation, 2) emerging evidence long been thought to be a static mark, recent studies suggests that DNA methylation is involved in the trans- indicate that methylated DNA undergoes dynamic and generational passage of obesity and other metabolic reversible remodeling through DNA demethylases, namely, disorders, 3) DNA methylation is involved in regulating the ten-eleven translocation (TET) proteins. Mounting the altered transcriptional landscape of dysfunctional evidence supports that DNA methylation is involved in adipose tissue, 4) genome-wide studies reveal specific various forms of metabolic perturbation, from the abnor- DNA methylation events that associate with obesity and mal development of adipose tissue to the dysfunction of T2D, and 5) the enzymatic effectors of DNA methylation adult adipocytes. Here, we will discuss the DNA methyl- have physiological functions in adipose development ation events that impact metabolism and the functional and metabolic function. roles of DNMTs and TET proteins in adipose biology, with an emphasis on those that may be associated with obesity and T2D. EPIGENETIC CHANGES ARE LINKED TO OBESITY DNA METHYLATION AND ITS MACHINERY AND TYPE 2 DIABETES DNA methylation is a process by which methyl groups are Obesity and type 2 diabetes (T2D) are highly complex added to the DNA molecule, especially at the 5 carbon of human diseases, and genetics plays an important role in the cytosine ring, which forms 5-methylcytosine (5mC) the etiology of both. With the advent of next-generation (7). In mammals, 5mC is mostly found in the context of sequencing, several common single nucleotide polymor- paired symmetrical methylation of a CpG site, a site in phisms (SNPs) have been discovered in association with which a cytosine is located next to a guanidine (7). disease susceptibility. However, the vast majority of these However, non-CpG methylation is also detected in human Department of Nutritional Sciences and Toxicology, University of California, © 2019 by the American Diabetes Association. Readers may use this article as long Berkeley, Berkeley, CA as the work is properly cited, the use is educational and not for profit, and the Corresponding author: Sona Kang, [email protected] work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Received 3 December 2018 and accepted 29 January 2019 872 DNA Methylation in Adipose Biology Diabetes Volume 68, May 2019 and other species (8–10). In the bulk of genomic DNA, DNA methylation at the regulatory regions is often asso- most CpGs are methylated, whereas those located in a CpG ciated with gene repression (17). island (where CpG sites cluster to form repetitive sequences) remain largely unmethylated (7). DNA METHYLATION IN ADIPOGENESIS DNA methylation is mediated by DNMTs. In mammals, DNA methylation plays an important role in a broad fi ve family members of the DNMT proteins have been scope of developmental processes including adipogenesis — — characterized Dnmt1,-2,-3a,-3b, and -3L yet only the (18–21). Inhibiting DNMT in multipotent C3H10T1/2 fi rst three possess DNMT activity (11). DNMT1 is the cells and 3T3-L1 preadipocytes stimulates spontaneous maintenance Dnmt for replication, whereas DNMT3a and differentiation and enhances differentiation in response -3b are referred as de novo DNMTs, as they can establish to adipogenic inducers (22,23). However, genetic studies a new DNA methylation pattern (11). The DNMT3-like have conflicting results with regard to the exact role of protein Dnmt3L is homologous to the other Dnmt3s but DNMTs in adipogenesis. DNMT1 is crucial for maintaining lacks catalytic activity, and Dnmt2 has sequence homology DNA methylation and repressive histone H3K9 methyl- to all Dnmts but methylates cytoplasmic tRNA instead of ation patterns prior to differentiation, suggesting it DNA (11). represses 3T3-L1 adipogenesis (24). However, knocking DNA methylation has long been thought to be a static down Dnmt1 and -3a impairs 3T3-L1 adipogenesis (25). epigenetic mark, but emerging evidence suggests that it This discrepancy might be due to the experimental con- undergoes dynamic and reversible remodeling in somatic ditions and tissue culture variables between the two cells during developmental and pathogenic processes laboratory environments. In another controversy, it was (12,13), making its machinery and effects attractive found that, in late-stage differentiation, DNMT inhibition drug targets. For example, DNA methylation can be erased promoted lipid accumulation by enhancing lipogenesis by by either passive or active mechanisms or a combination of upregulating the lipogenic transcription factor Srebp1c both (14). Passive demethylation is often due to the loss of (25). By contrast, other groups reported that DNMT in- 5mC during successive rounds of replication in the absence hibition reduced adipogenic capacity in 3T3-L1 and ST2 of methylation maintenance machinery such as DNMT1. mesenchymal precursor cell lines by upregulating canon- By contrast, active demethylation is mediated by a set of ical Wnt signaling (21,26). enzymes; TET proteins (TET1, -2, and -3) oxidize 5mC to Fortunately, there is more consensus in the field about hydroxymethylcytosine (5hmC), which is then converted the DNA methylation profile of key adipocyte genes during to unmethylated cytosine (5C) through base excision re- differentiation (Fig. 1). PPARg is expressed mainly in pair and thymidine DNA glycosylase (15). adipose tissue, where it regulates fatty acid storage and The biological importance of DNA methylation as a ma- glucose metabolism, and C/EBP is involved in adipogen- jor type of epigenetic modification in regulating gene esis. The promoters of both genes are gradually demethy- expression has been well established. In general, reduced lated during 3T3-L1 adipogenesis, correlating with increased DNA methylation in the promoter or other gene regulatory expression of the genes (27,28). This coincides with the regions is associated with increased DNA binding of tran- loss of repressive histone marks (H3K9me3) and the scription factors and chromatin proteins, thus allowing gain of active marks (e.g., H3K27ac and H3K4me3) gene transcription to occur (16). By contrast, increased (28), although the regulation of this timing is not clearly Figure 1—Summary of the relationship between environmental factors and DNA (de)methylation machinery in the regulation of adipose biology. Various perturbations from environmental cues affect the expression or activity of DNMTs and TETs, which alters the DNA methylation profile of specific target genes with concordant changes in gene expression and phenotypic changes in adipose biology. The dotted line is used to depict relationships with weaker evidence. Small arrow inserts indicate the direction of change in DNA methylation at affected genes. Plus and minus signs indicate the direction of gene expression change. diabetes.diabetesjournals.org Ma and Kang 873 understood. In addition, dexamethasone treatment causes to the Ucp1 enhancer and promoter regions for gene Cebpa demethylationinC3H10T1/2cells,withaconcor- repression (42). Consistently, treatment of 3T3-L1 and dant release of DNMT3a and -3b from the promoter (28). mouse embryonic fibroblasts with DNMT inhibitor increases It is also noteworthy that the gene bodies of both Pparg Ucp1 expression. Furthermore, TET-mediated DNA deme- and Cebpa are highly hypermethylated in embryonic stem thylation is required for the gene activation of Prdm16,an cells to restrict lineage commitment to adipogenesis (29). important transcriptional regulator of brown adipose
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