Review
Epigenetic regulation of adipogenesis by histone methylation

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Abstract

Histone methylation is implicated in both gene activation and repression, depending on the specific lysine residue that gets methylated. Recent years have witnessed an explosive expansion of the list of remarkably site-specific histone methyltransferases and demethylases, which greatly facilitates the study on the biological functions of histone methylation in gene expression and cell differentiation in mammalian cells. Adipogenesis represents an excellent model system to understand transcriptional and epigenetic regulation of gene expression and cell differentiation. While transcriptional regulation of adipogenesis has been extensively studied, the roles of epigenetic mechanisms in particular histone methylation in regulation of adipogenesis have just begun to be understood. This review will summarize the recent progress on epigenetic regulation of adipogenesis by histone methylation, with a focus on histone H3K4 and H3K27. The available evidence suggests that site-specific histone methylations play critical roles in adipogenesis and control the expression of both positive and negative master regulators of adipogenesis. This article is part of a Special Issue entitled: Chromatin in time and space.

Highlights

► Histone methylations regulate gene expression and cell differentiation. ► Histone methylations are regulated by methyltransferases and demethylases. ► This review focuses on regulation of adipogenesis by histone methylation. ► H3K4 and H3K27 methylations control expression of master regulators of adipogenesis.

Introduction

Type 2 diabetes, which accounts for 90–95% of all diabetes, is one of the leading causes of morbidity and mortality worldwide. Obesity is the single most important risk factor for type 2 diabetes. Understanding the molecular mechanisms underlying adipogenesis (generation of fat tissue) may lead to novel approaches to the treatment of obesity and lipodystrophy, the two diseases that are tightly associated with type 2 diabetes. Transcriptional regulation of adipogenesis has been extensively reviewed [1], [2]. This review will focus on the role of histone lysine methylation in regulation of adipogenesis. I start with an introduction on the dynamic regulation of histone methylations by site-specific histone methyltransferases and demethylases. After a brief overview of the major positive and negative regulators of adipogenesis, I discuss the roles of histone methylations in particular histone H3K4 and H3K27 methylations, and the associated histone methyltransferases and demethylases, in controlling the expression of the master positive and negative regulators of adipogenesis.

Section snippets

Dynamic regulation of histone methylation by site-specific methyltransferases and demethylases

Epigenetic mechanisms, including histone modifications (such as acetylation, methylation and phosphorylation) (Fig. 1), chromatin remodeling, histone variant incorporation, non-coding RNAs and DNA methylation, play critical roles in regulating both global and tissue- and developmental stage-specific gene expression [3]. Histone acetylation occurs on lysine (K) residues and is dynamically regulated by histone acetyltransferases (HATs) and deacetylases [4]. Recent evidences suggest that although

Positive and negative regulators of adipogenesis

Adipocytes are believed to derive from multipotent mesenchymal stem cells (MSCs). Differentiation of MSCs to adipocytes involves two stages: determination and terminal differentiation. Determination refers to the commitment of MSCs to the adipocyte lineage, which results in the conversion of MSCs into preadipocytes. In the terminal differentiation stage, the fibroblast-like preadipocytes differentiate and convert into fat-laden adipocytes [2].

Much of our knowledge on adipogenesis comes from

Regulation of adipogenesis by H3K4 methylation

Mono-, di- and tri-methylations on histone H3K4 (H3K4me1, H3K4me2 and H3K4me3, respectively) are generally correlated with gene activation. Genome-wide analyses show that H3K4me1 and H3K4me2 are associated with open chromatin and are often enriched on cis-regulatory regions [22]. H3K4me1, along with H3K27ac, is often enriched on enhancers [23]. H3K4me3 is enriched around transcription start sites and correlates well with gene expression level [24]. PPARγ has mainly two isoforms, PPARγ1 and

Regulation of adipogenesis by H3K27 methylation

Tri-methylation on H3K27 (H3K27me3) is a repressive epigenetic mark important for Polycomb-mediated gene silencing [11]. The mammalian Polycomb repressive complex 2 (PRC2) uses its enzymatic subunit Ezh2 to specifically methylate H3K27. Ezh2 is responsible for the majority of H3K27me2 and H3K27me3 in cells [37], [38]. Genome-wide analyses have shown that Ezh2 and H3K27me3 are enriched on a large number of developmental regulators in embryonic stem cells and other cell types [39], [40]. In

Summary

Methylations on histone H3K4 are generally associated with gene activation whereas methylations on H3K27 are generally associated with gene repression. PTIP, a protein that associates with histone H3K4 methyltransferases MLL3/MLL4 and histone H3K27 demethylase UTX, is required for PPARγ and C/EBPα expression and adipogenesis [27]. The histone H3K27 methyltransferase PRC2 uses its enzymatic subunit Ezh2 to repress Wnt genes and facilitate adipogenesis [38]. Together, these results provide an

Future directions

PPARγ and Wnts are master positive and negative regulators of adipogenesis, respectively. The H3K4 methylation regulator PTIP promotes PPARγ expression while the H3K27 methyltransferase Ezh2 represses Wnt expression during adipogenesis (Fig. 4). However, the epigenetic factors that repress PPARγ but promote Wnt expression in preadipocytes have not been identified. Analyzing the enrichment and/or the dynamic changes of histone methylation patterns on PPARγ and Wnt promoters in preadipocytes and

Acknowledgements

Research in Kai Ge laboratory was supported by the Intramural Research Program of the NIDDK, NIH.

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    This article is part of a Special Issue entitled: Chromatin in time and space.

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