The vast majority of histone methyltransferases and demethylases were identified in the 21st century but their biological functions are poorly understood. We use adipogenesis as a model system to study the roles of histone methyltransferases and demethylases, and the dynamics of site-specific histone methylation, in regulation of gene expression and cell differentiation. We are interested in methylations on K4, K9, K27 and K36 of histone H3 (H3K4, H3K9, H3K27 and H3K36, respectively). The Polycomb repressive complex 2 (PRC2) is a major regulator of animal development. PRC2 represses gene expression mainly through its enzymatic subunit Ezh2-mediated tri-methylation on H3K27 (H3K27me3). Using Ezh2 conditional KO preadipocytes, we report that Ezh2 and its H3K27 methyltransferase activity are required for adipogenesis and that Ezh2 constitutively represses Wnt genes to facilitate adipogenesis (Wang L, PNAS 2010). Histone methyltransferase G9a is responsible for H3K9 di-methylation (H3K9me2), an epigenetic mark for gene repression. Using G9a conditional KO preadipocytes, we report recently that G9a represses PPARgamma expression and adipogenesis. G9a regulates both positive and negative master regulators of adipogenesis: G9a represses PPARgamma expression dependent on its H3K9 methyltransferase activity while promotes Wnt expression independent of its enzymatic activity (Wang L, EMBO J 2013). Together with our reports that H3K4me1/2 methyltransferases MLL3/MLL4 are required for PPARgamma and C/EBPalpha expression and adipogenesis (Lee JE, eLife 2013), these findings provide an initial view of epigenetic regulation of adipogenesis, and suggest that histone methylations control expression of positive and negative master regulators of adipogenesis (reviewed in BBA 2012 and Cell & Biosci 2014). Histone acetyltransferase (HAT) Gcn5 is critical for embryogenesis and shows partial functional redundancy with its homolog PCAF. However, the tissue- and cell lineage-specific functions of Gcn5 and PCAF are still not well defined. In a recent study, we probe the functions of Gcn5 and PCAF in adipogenesis. We found that the double knockout (DKO) of Gcn5/PCAF inhibits expression of the master adipogenic transcription factor gene PPARgamma, thereby preventing adipocyte differentiation. The adipogenesis defects in Gcn5/PCAF DKO cells are rescued by ectopic expression of PPARgamma, suggesting Gcn5/PCAF act upstream of PPARgamma to facilitate adipogenesis. The requirement of Gcn5/PCAF for PPARgamma expression was unexpectedly bypassed by prolonged treatment with an adipogenic inducer, 3-isobutyl-1-methylxanthine (IBMX). However, neither PPARgamma ectopic expression nor prolonged IBMX treatment rescued defects in Prdm16 expression in DKO cells, indicating that Gcn5/PCAF are essential for normal Prdm16 expression. Gcn5/PCAF regulate PPARgamma and Prdm16 expression at different steps in the transcription process, facilitating RNA polymerase II recruitment to Prdm16 and elongation of PPARgamma transcripts. Overall, our study reveals that Gcn5/PCAF facilitate adipogenesis through regulation of PPARgamma expression and regulate brown adipogenesis by influencing Prdm16 expression (Jin Q. et al., 2014).

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Zhuang, Lenan; Jang, Younghoon; Park, Young-Kwon et al. (2018) Depletion of Nsd2-mediated histone H3K36 methylation impairs adipose tissue development and function. Nat Commun 9:1796
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