Ellagic acid attenuates adipocyte differentiation via histone arginine methylation‐associated epigenetic modification (271.2)

Abstract

Previously, we have demonstrated that ellagic acid (EA), a naturally occurring polyphenol in numerous fruits and vegetables, represses adipogenic conversion of human adipose‐derived stem cells (hASCs) by altering epigenetic factors. However, the detailed mechanism by which EA attenuates adipocyte differentiation is largely unknown. In this study, we first hypothesized that upregulation of HDAC9 by EA is the key mechanism to inhibit adipogenesis. Unexpectedly, knockdown HDAC9 by siRNA had marginal impact on recovering adipogenesis. Intriguingly, EA treatment was associated with reduced histone 3 arginine 17 methylation levels (H3R17me2), implying the inhibitory role of EA in CARM1 (coactivator associated arginine methyltransferase 1) activity. To test the hypothesis that recovery of H3R17me2 will rescue EA‐mediated inhibition of adipogenesis, cell‐penetrating peptides of CARM1 (CPP‐CARM1) was delivered to compensate the loss of CARM1 activity by EA. Delivery of CPP‐CARM1 was able to restore H3R17me2, HDAC9 dissociation, histone acetylation levels, 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.Grant Funding Source: Supported by USDA‐HATCH