H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers
- Columbia University, United States
- Mayo Clinic, United States
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 H3K27 trimethylation, and hence silencing of tumor suppressor genes.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE94834
Article and author information
Author details
Funding
National Institutes of Health (CA204297)
- Zhiguo Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jerry L Workman, Stowers Institute for Medical Research, United States
Version history
- Received: March 15, 2018
- Accepted: June 21, 2018
- Accepted Manuscript published: June 22, 2018 (version 1)
- Version of Record published: July 5, 2018 (version 2)
Copyright
© 2018, Fang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers
eLife 7:e36696.
https://doi.org/10.7554/eLife.36696
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