Like all cell differentiation processes, adipogenesis is tightly regulated through epigenetic modifications, which control whether a given gene is expressed or repressed. Previous work had revealed epigenetic mechanisms that promote the expression of peroxisome proliferator activated receptor-γ (PPARγ), the master regulator of adipogenesis. Here, Ge and colleagues reveal that the histone methyltransferase G9A (also known as EHMT2) blocks PPARγ expression through the addition of an epigenetic mark and also promotes the expression of WNT10A, a negative regulator of adipogenesis.
G9A is primarily responsible for histone H3 dimethylation at Lys9 (H3K9me2), which is thought to promote gene silencing. The authors observed that H3K9me2 levels were high specifically on the Pparg locus but were low on genes encoding other regulators of adipogenesis. Moreover, H3K9me2 levels on Pparg markedly decreased during adipocyte differentiation. Consistent with this, G9A was enriched throughout the promoter and gene body regions of both PPARγ isoforms (Pparg1 and Pparg2). Moreover, G9A deletion significantly increased Pparg2 expression by promoting the binding of the transcription factor C/EBPβ (CCAAT/enhancer-binding protein-β) to the Pparg2 promoter, ultimately enhancing adipogenesis. Together, these findings suggest that G9A inhibits adipogenesis by adding a repressive H3K9me2 mark on the Pparg promoter.
Interestingly, the authors observed that depletion of G9A also decreased the expression of WNT10A and attenuated canonical WNT signalling, which is thought to inhibit adipogenesis. This effect could be rescued through the addition of G9A or of G9A lacking enzymatic activity. Similarly, administration of the G9A inhibitor BIX01294 — which specifically interferes with the methyltransferase activity and decreases H3K9me2 levels — increased Pparg expression but had no effect on WNT10A expression. Thus, G9A seems to promote WNT10A expression independently of its enzymatic activity.
Finally, the authors confirmed their findings ex vivo. They observed that white preadipocytes isolated from G9A-knockout mice showed enhanced adipogenesis and increased expression of Pparg and of other adipogenic markers.
So, G9A seems to repress adipogenesis by targeting two fronts: inhibiting Pparg expression and promoting Wnt10a expression. Further work is now needed to determine how G9A itself is targeted to the Pparg locus.
References
ORIGINAL RESEARCH PAPER
Wang, L. et al. Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J. 23 Nov 2012 (doi:10.1038/emboj.2012.306)
FURTHER READING
Cristancho, A. G. & Lazar, M. A. Forming functional fat: a growing understanding of adipocyte differentiation. Nature Rev. Mol. Cell Biol. 12, 722–734 (2011)
Rights and permissions
About this article
Cite this article
David, R. G9A covers all bases. Nat Rev Mol Cell Biol 14, 5 (2013). https://doi.org/10.1038/nrm3497
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm3497
This article is cited by
-
Expression of G9a in Auditory Cortex Is Downregulated in a Rat Model of Age-Related Hearing Loss
Journal of Molecular Neuroscience (2021)
-
G9a/RelB regulates self-renewal and function of colon-cancer-initiating cells by silencing Let-7b and activating the K-RAS/β-catenin pathway
Nature Cell Biology (2016)