Article

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: 9.81). 04/2010; 107(16):7317-22. DOI: 10.1073/pnas.1000031107
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: I-hsin Su, Mar 11, 2015
0 Followers
 · 
110 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have recently generated knockout mice for the Cbx7 gene, coding for a polycomb group protein that is downregulated in human malignant neoplasias. These mice develop liver and lung adenomas and carcinomas, which confirms a tumour suppressor role for CBX7. The CBX7 ability to downregulate CCNE1 expression likely accounts for the phenotype of the Cbx7-null mice. Unexpectedly, Cbx7-knockout mice had a higher fat tissue mass than wild-type, suggesting a role of CBX7 in adipogenesis. Consistently, we demonstrate that Cbx7-null mouse embryonic fibroblasts go towards adipocyte differentiation more efficiently than their wild-type counterparts, and this effect is Cbx7 dose-dependent. Similar results were obtained when Cbx7-null embryonic stem cells were induced to differentiate into adipocytes. Conversely, mouse embryonic fibroblasts and human adipose-derived stem cells overexpressing CBX7 show an opposite behaviour. These findings support a negative role of CBX7 in the control of adipocyte cell growth and differentiation.
    Biology Open 09/2014; 3(9). DOI:10.1242/bio.20147872 · 2.42 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chromatin remodeling is a key mechanism in adipocyte differentiation. However, it is unknown whether dietary polyphenols are epigenetic effectors for adiposity control. Ellagic acid (EA) is a naturally occurring polyphenol in numerous fruits and vegetables. Recently, EA-containing foods have been reported to reduce adiposity. In the present study, we sought to determine whether EA inhibits adipogenesis by modifying chromatin remodeling in human adipogenic stem cells (hASCs). qPCR microarray of chromatin modification enzymes revealed that 10 μmol/L of EA significantly inhibits histone deacetylase (HDAC) 9 down-regulation. In addition, EA was associated with up-regulation of HDAC activity and a marked reduction of histone acetylation levels. However, chemical inhibition of HDAC activity or depletion of HDAC9 by siRNA were not sufficient to reverse the anti-adipogenic effects of EA. Intriguingly, EA treatment was also associated with reduced histone 3 arginine 17 methylation levels (H3R17me2), implying the inhibitory role of EA in coactivator-associated arginine methyltransferase 1 (CARM) 1 activity during adipogenesis. Boosting CARM1 activity by delivering cell-penetrating peptides of CARM1 (CPP-CARM1) not only recovered H3R17me2, but also restored adipogenesis evidenced by H3 acetylation at lysine 9 (H3K9Ac), HDAC9 down-regulation, PPARγ expression, and triglyceride accumulation. Taken together, our data suggest that reduced CARM1 activity by EA results in a decrease of H3R17me2 levels, which may interrupt consecutive histone remodeling steps for adipocyte differentiation including histone acetylation and HDAC9 dissociation from chromatin. Our work provides the mechanistic insights into how EA, a polyphenol ubiquitously found in fruits and vegetables, attenuates human adipocyte differentiation by altering chromatin remodeling.
    The Journal of nutritional biochemistry 09/2014; 25(9). DOI:10.1016/j.jnutbio.2014.04.008 · 4.59 Impact Factor
  • Source
    • "For example , HOTAIR interacts with PRC2 (polycomb repressive complex 2) and histone demethylases LSD1/CoREST/REST complexes through it 5 -and 3 -end, respectively [7] [11]. Notably, PRC2 complex that contains histone H3-lysine 27 (H3K27)-specific histone methylases EZH2, along with several other polycomb group (PcG) of proteins [12]. LSD1 is a histone H3K4-specific demethylase [13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo.
    The Journal of steroid biochemistry and molecular biology 05/2014; 141. DOI:10.1016/j.jsbmb.2014.02.002 · 4.05 Impact Factor
Show more