Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis

Nuclear Receptor Biology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2010; 107(16):7317-22. DOI: 10.1073/pnas.1000031107
Source: PubMed


Wnt/beta-catenin signaling inhibits adipogenesis. Genome-wide profiling studies have revealed the enrichment of histone H3K27 methyltransferase Ezh2 on Wnt genes. However, the functional significance of such a direct link between the two types of developmental regulators in mammalian cells, and the role of Ezh2 in adipogenesis, remain unclear. Here we show Ezh2 and its H3K27 methyltransferase activity are required for adipogenesis. Ezh2 directly represses Wnt1, -6, -10a, and -10b genes in preadipocytes and during adipogenesis. Deletion of Ezh2 eliminates H3K27me3 on Wnt promoters and derepresses Wnt expression, which leads to activation of Wnt/beta-catenin signaling and inhibition of adipogenesis. Ectopic expression of the wild-type (WT) Ezh2, but not the enzymatically inactive F667I mutant, prevents the loss of H3K27me3 and the defects in adipogenesis in Ezh2(-/-) preadipocytes. The adipogenesis defects in Ezh2(-/-) cells can be rescued by expression of adipogenic transcription factors PPARgamma, C/EBPalpha, or inhibitors of Wnt/beta-catenin signaling. Interestingly, Ezh2(-/-) cells show marked increase of H3K27 acetylation globally as well as on Wnt promoters. These results indicate that H3K27 methyltransferase Ezh2 directly represses Wnt genes to facilitate adipogenesis and suggest that acetylation and trimethylation on H3K27 play opposing roles in regulating Wnt expression.

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Available from: I-hsin Su, Mar 11, 2015
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    • "Deletion of Ezh2 eliminates H3K27me3 on Wnt promoters and derepresses Wnt expression, which leads to activation of Wnt/b-catenin signaling and inhibition of adipogenesis. Ectopic expression of the WT Ezh2, but not the enzymatically inactive F667I mutant, prevents the loss of H3K27me3 and the defective adipogenesis in Ezh2 2/2 preadipocytes (Wang et al., 2010). Moreover, the involvement of the polycomb family protein in adipogenic differentiation seems also supported by data reporting histone H3 modifications associated with differentiation and long-term culture of mesenchymal adipose stem cells. "
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    • "In the presence of EA, the inhibited CARM1 activity by EA results in the suppression of H3R17 methylation, which in turn abolishes H3K9 acetylation and HDAC9 dissociation, and ultimately represses adipogenesis. Extensive research from several groups has identified that histone-modifying enzymes play pivotal roles in adipocyte development: (a) deletion of histone methyl-transferase enhancer of zeste homolog (Ezh2) abolished trimethylation on H3K27 of Wnt promoter region, resulting in constitutive activation of Wnt signaling and transcriptional inhibition of adipogenesis [24]; (b) silencing of PRMT5 repressed adipogenic gene expression, which was reversed by PRMT5 overexpression [26]; (c) histone methyltransferase G9a seemed to play dual roles for turning on or off adipogenic signaling based on its methylation sites by serving as a coactivator or co-repressor [49]; (d) Class II HDACs have been reported to control PPARγ signaling [50]. Among the Class II HDACs, HDAC9 has been identified as a unique transcriptional co-repressor on C/EBPα promoter [28]; and (e) mice born with the deletion of CARM1 lacked in fat pad development [51] [52] identifying the adipose-specific role of CARM1 as a coactivator for PPARγ [25]. "
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    • "In particular, EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), induces histone methyltransferase activity primarily by trimethylating histone H3 at lysine 27 (H3K27me3), hence mediating gene silencing. PcGs are crucial in the chromatin control of stem cell self-renewal and differentiation [1]–[7]. They also play a crucial role in malignant progression and are implicated in cancer metastasis [8]. "
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