The H3K36me2 writer-reader dependency in H3K27M-DIPG

Yu, Jia-Ray, LeRoy, Gary, Bready, Devin, Frenster, Joshua D., Saldaña-Meyer, Ricardo, Jin, Ying, Descostes, Nicolas, Stafford, James M., Placantonakis, Dimitris G., Reinberg, Danny (July 2021) The H3K36me2 writer-reader dependency in H3K27M-DIPG. Science Advances, 7 (29). ISSN 2375-2548

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URL: https://pubmed.ncbi.nlm.nih.gov/34261657/
DOI: 10.1126/sciadv.abg7444

Abstract

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > histone
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL Cancer Center Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
Depositing User: Sasha Luks-Morgan
Date: 14 July 2021
Date Deposited: 15 Jul 2021 17:09
Last Modified: 13 Feb 2024 19:41
PMCID: PMC8279504
URI: https://repository.cshl.edu/id/eprint/40294

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