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

ABSTRACT: The epigenetic mechanisms regulating adipose tissue development and function are poorly understood. In this study, we show that depletion of histone H3K36 methylation by H3.3K36M in preadipocytes inhibits adipogenesis by increasing H3K27me3 to prevent the induction of C/EBP? and other targets of the master adipogenic transcription factor peroxisome proliferator-activated receptor-? (PPAR?). Depleting H3K36 methyltransferase Nsd2, but not Nsd1 or Setd2, phenocopies the effects of H3.3K36M on adipogenesis and PPAR? target expression. Consistently, expression of H3.3K36M in progenitor cells impairs brown adipose tissue (BAT) and muscle development in mice. In contrast, depletion of histone H3K36 methylation by H3.3K36M in adipocytes in vivo does not affect adipose tissue weight, but leads to profound whitening of BAT and insulin resistance in white adipose tissue (WAT). These mice are resistant to high fat diet-induced WAT expansion and show severe lipodystrophy. Together, these results suggest a critical role of Nsd2-mediated H3K36 methylation in adipose tissue development and function.

SUBMITTER: Zhuang L

PROVIDER: S-EPMC5935725 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Zhuang Lenan L Jang Younghoon Y Park Young-Kwon YK Lee Ji-Eun JE Jain Shalini S Froimchuk Eugene E Broun Aaron A Liu Chengyu C Gavrilova Oksana O Ge Kai K

Nature communications 20180504 1

The epigenetic mechanisms regulating adipose tissue development and function are poorly understood. In this study, we show that depletion of histone H3K36 methylation by H3.3K36M in preadipocytes inhibits adipogenesis by increasing H3K27me3 to prevent the induction of C/EBPα and other targets of the master adipogenic transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). Depleting H3K36 methyltransferase Nsd2, but not Nsd1 or Setd2, phenocopies the effects of H3.3K36M on adip ...[more]

PMID: 29728617

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Project description:Histone tails are post-translationally modified at multiple sites, including Lys36 on histone H3 (H3K36). The H3K36 methylation has been shown to associate with the transcription of active euchromatin, alternative splicing, DNA repair and recombination. However, the role of H3K36 methylation during cell differentiation is still obscure.Previous investigations found that a site specific Lys-to-Met mutation on histones can serve as an inhibitor of this site specific methyltransferases to repress global methylation on that lysine of histones. In this study we usedH3K36 Lys-to-Met mutant (H3K36M) as a tool to investigaterole of H3K36 methylation in our cell differentiation system. Expression of H3K36M repressed global H3K36 methylation but increased H3K27me3 as previously reported. On our cell differentiation system, H3K36M suppressed adipogenesis and myogenesis. Our pioneer RNA-seqstudy further showed that H3K36M repressed the expression of master regulator genes. Here, we did ChIP-seq of several histone modifications to further explore the changes on the epigenome by expression of H3K36M. Interestingly, on some important master regulator genes loci, the repressive marker H3K27me3 increased significantly, correlated with the repression on their expression. The H3K36M decreases global H3K36 di- and tri-methylation. To clarify which H3K36 methyltransferase is important for cell differentiation, we knocked down H3K36 di-methyltransferases Nsd1 and Nsd2, H3K36 tri-methyltransferase Setd2 separately. Nsd2 knockdown, but not Nsd1 or Setd2,can phenocopythe adipogenesis defect in H3K36M expressed cells.Comparing in RNA-seq results, Nsd2 knockdown cells showed similar gene expression profile with H3K36M expressed cells in adipogenesis. These suggest that Nsd2-mediated H3K36me2 plays an important role in adipogenesis.To study the role of H3K36 methylation in vivo, we generated an aP2 promoter driven H3K36M expressed transgenic mouse (Tg), to express H3K36M specifically in adipose tissue. The Tg mice showedsignificant dysfunction in both white and brown adipose tissues. Their fat tissues gene expression profile changed significantly. All of these indicate that H3K36 methylation is important for adipose tissue developmentin vivo.Together, our comprehensive studies provide novel insights into dynamics of H3K36 methylation and its important role in transcriptional regulation of cell differentiation and mouse fat tissue development.

Dataset Information

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

Publications

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

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