MacroH2A1.1 cooperates with EZH2 to promote adipogenesis by regulating Wnt signaling

Abstract

White adipocytes play important roles in many physiological processes, including energy storage, endocrine signaling, and inflammatory responses. Understanding the molecular mechanisms of adipocyte formation (adipogenesis) provides insights into therapeutic approaches against obesity and its related diseases. Many transcriptional factors and epigenetic enzymes are known to regulate adipogenesis; however, whether histone variants play a role in this process is unknown. Here we found that macroH2A1.1 (mH2A1.1), a variant of histone H2A, was upregulated during adipocyte differentiation in 3T3-L1 cells and in the white adipose tissue of obese mice. Ablation of mH2A1.1 activated Wnt/β-catenin signaling pathway, while overexpression of mH2A1.1 showed opposite effects. We further found that mH2A1.1 regulated Wnt/β-catenin signaling pathway by cooperating with EZH2, a histone H3K27 methyltransferase, thus led to accumulation of H3K27me2 and H3K27me3 on the promoters of Wnt genes. Mutations in the macro-domain, mH2A1.1G224E, and mH2A1.1G314E, not only impaired adipogenesis, but also impaired the binding ability of mH2A1.1 to EZH2 and the enrichments of H3K27me2 and H3K27me3 on the promoters of Wnt genes. Together, our study reveals a novel regulatory role of mH2A1.1 in adipogenesis and obesity, which provides new insights in white fat development.

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

“…The relative difference was expressed as the fold change calculated by the 2 −ΔΔCT method (Wan et al . ).…”

“…MES13 cells were cross‐linked using 1% formaldehyde and stopped by adding glycine, and the ChIP assay was performed as described previously (Wan et al . ). Chromatin was immunoprecipitated with H3K27me3 antibody (catalogue no.…”

“…293T cells were treated with or without 300 μ m PA for 48 h before collection, the co‐immunoprecipitation assay was performed as described previously (Wan et al . ). UTX antibody (catalogue no.…”

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

“…3T3-L1 cells were cultured and differentiated as we previously reported. 16,22 Mouse 3T3-L1 cells were cultured in DMEM media (Hyclone, South Logan, UT) supplemented with 10% newborn bovine serum (Gibco) and 1% penicillin/ streptomycin (Hyclone). Confluent 3T3-L1 cells (counted as Day -2) went through contact inhibition for 2 days and were induced in DMEM containing 10% FBS, 0.5 mM 3-isobutylmethylxanthine (Sigma), 1 mM dexamethasone (Sigma), 10 μg/mL insulin (Sigma) for 96 hours.…”

Histone methyltransferase G9a protects against acute liver injury through GSTP1

“…ChIP assay was performed as we previously described [12]. Briefly, liver tissues were minced and crosslinked with 1% formaldehyde, then quenched with 125 mM glycine.…”