H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers

Dong Fang, Haiyun Gan, Liang Cheng, Jeong Heon Lee, Hui Zhou, Jann N Sarkaria, David Daniels, Zhiguo Zhang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

Original languageEnglish (US)
Article numbere36696
JournaleLife
Volume7
DOIs
StatePublished - Jun 22 2018

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Mutant Proteins
Tumor Suppressor Genes
Glioma
Tumors
Wilms Tumor
Genes
Histones
Methylation
Carcinogenesis
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers. / Fang, Dong; Gan, Haiyun; Cheng, Liang; Lee, Jeong Heon; Zhou, Hui; Sarkaria, Jann N; Daniels, David; Zhang, Zhiguo.

In: eLife, Vol. 7, e36696, 22.06.2018.

Research output: Contribution to journalArticle

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AU - Zhou, Hui

AU - Sarkaria, Jann N

AU - Daniels, David

AU - Zhang, Zhiguo

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