Role of histone methylation and demethylation in adipogenesis and obesity

Abstract

Adipocyte differentiation is a complex developmental process that involves the coordinated interplay of numerous transcription factors. PPARγ has emerged as a master regulator of adipogenesis and recent global target gene analysis demonstrated that PPARγ targets many genes encoding chromatin modification enzymes as well as genes of lipid metabolism and storage. Among such modification enzymes are histone lysine methyltransferases, which play important roles in transcriptional regulation. Histone methyltransferases are involved in PPARγ gene expression and subsequent adipogenesis. In addition, recent studies revealed that demethylation of histone H3 at lys9 is associated with resistance to obesity. We here review the role of histone methylation and demethylation in adipogenesis, metabolism and obesity.

Keywords: PR-Set7; Setd8; Setdb1; Wnt; adipogenesis; epigenetics; histone lysine methyltransferase (HKMT); metabolic syndrome; obesity; peroxisome proliferator-activated receptor (PPAR).

Figure 1

Models for the coordinate regulation of transcription and histone modification by PPARγ for adipogenesis. Two well characterized HKMT, Setdb1 and Setd8 are coordinately regulated by PPARγ and their increased activity facilitates terminal adipocyte differentiation through chromatin modification. PPARγ also drives induction of PPARγ2 via a feedback loop and many other of the target genes via two pathways; one through transcription and the other, by way of an epigenetic pathway. PPARγ requires Setd8 to acquire H4K20me1 modification in order to enhance its transcription, while Setd8 requires PPARγ to be transcriptionally induced. These two are both required for the expression of PPARγ targets. Setdb1 is an anti-adipogenic factor whose expression is downregulated toward the end of differentiation. Setdb1 is also identified as a PPARγ target, however, it remains to be determined whether it is a direct downregulated target genes.

Figure 2

A mechanistic model for noncanonical Wnt5a dependent suppression of PPARγ function. CaMKII, calcium/calmodulin-dependent protein kinase II; TAK1, TGFβ-activating kinase 1; TAB2 = TAK1-binding protein 2; NLK, nemo-like kinase.

Figure 3

A schematic model for canonical Wnt and β-catenin mediated suppression of PPARγ gene expression. LRP, low-density lipoprotein receptor-related protein; GSK3, serine/threonine kinase glycogen synthase kinase-3; APC, adenomatous polyposis coli; Dsh, Dishevelled; TCF, T cell factor.