Depletion of Nsd2-mediated histone H3K36 methylation reprograms adipose tissue development and function

Authors

• L Zhuang
• Y Jang
• Y Park
• J Lee
• S Jain
• E Froimchuk
• C Liu
• O Gavrilova
• K Ge

Abstract

Adipose tissue plays a critical role in regulating energy balance and glucose homeostasis. There are two major types of adipose tissues, white and brown. White adipose tissue (WAT) stores excess energy in the form of triglycerides. Brown adipose tissue (BAT) is specialized to expend energy to generate heat. Development of adipose tissue (adipogenesis) is under the control of transcriptional and epigenetic mechanisms. The master adipogenic transcription factor PPARgamma cooperates with C/EBPalpha to activate the expression of genes critical for adipogenesis. Epigenetic mechanisms, especially methylations on histone H3 lysine 4 (H3K4), H3K9 and H3K27, have also been implicated in regulating adipogenesis and adipocyte functions. However, the role of histone H3K36 methylation in adipogenesis and adipocyte function has remained unclear. It has been reported previously that ectopic expression of a histone H3.3 mutant with the lysine-to-methionine (K-to-M) mutation at K4, K9, K27 or K36 specifically depletes endogenous H3K4, H3K9, H3K27 or H3K36 methylation. In this study, we used four K-to-M mutants (K4M, K9M, K27M, and K36M) of histone H3.3 as tools to clarify the roles of site-specific histone methylation in adipogenesis. We found that depletion of H3K36 methylation by H3.3K36M leads to severe defects in adipogenesis. H3.3K36M inhibits adipogenesis by blocking the induction of C/EBPalpha and other PPARgamma target genes that are critical for adipogenesis. Knockout of H3K36 methyltransferase Nsd2 or inactivating its enzymatic activity phenocopies H3.3K36M expression, suggesting that H3.3K36M targets Nsd2 to inhibit adipogenesis. In mice, adipose tissue-selective expression of H3.3K36M leads to reprogrammed gene expression profile and profound whitening of BAT, which result in severe thermogenesis defects and cold intolerance. Depleting H3K36 methylation by H3.3K36M in WAT causes insulin resistance and renders mice resistant to high fat diet induced WAT expansion. These mice show severe lipodystrophy associated with hyperlipidemia, insulin resistance and diabetes. Together, our data suggest a critical role of H3K36 methylation in adipose tissue development and function.

Scientific Focus Area: Chromosome Biology

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