Double SET point: G9a makes its mark in adipogenesis

Abstract

EMBO J (2013) 32 1, 45–59 doi:; DOI: 10.1038/emboj.2012.306; published online November 23 2012

Sequence-specific DNA-binding transcription factors (TFs) bind throughout the genome to orchestrate the process of adipocyte differentiation in an exquisitely timed and precise manner. TF binding recruits histone-modifying enzymes, resulting in dynamic epigenomic modifications that correlate with extensive gene expression changes. In this issue of The EMBO Journal, Wang et al (2012) demonstrate a critical role for the SET-containing histone methyltransferase G9a in generating repressive chromatin marks that are lost in the process of adipogenesis.

Figure 1

G9a represses PPARγ levels in preadipocytes. In preadipocytes, the repressive H3K27me3 mark surrounds the PPARg locus, but Wang et al have shown that H3K9me2 is a repressive mark found throughout this region. G9a, an SET domain containing histone methyltransferase, is required for the deposition of H3K9me2 at this locus. However, the sequence-specific TF(s) that localize it to the genome are unknown. During early differentiation, as G9a levels begin to decrease and H3K9me2 levels also diminish at the PPARg locus, transcriptional activators of adipogenesis (C/EBPβ, C/EBPδ, GR and STAT5a) are recruited to enhancers at hotspots of open chromatin and epigenomic change, driving the increase in PPARγ levels. The exact temporal relation of changes in H3K9me2 levels to the epigenomic transition state remains to be determined. In mature adipocytes, the major sequence-specific positive regulators of adipogenesis (PPARγ, C/EBPα and C/EBPβ) bind enhancers characterized as regions with DNAse I hypersensitivity and histone modifications of active transcription, like H3K9ac and H3K27ac, H3K9me2 is no longer present and robust PPARγ expression is sustained.