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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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: | |
| Depositing User: | Sasha Luks-Morgan |
| Date: | 14 July 2021 |
| Date Deposited: | 15 Jul 2021 17:09 |
| Last Modified: | 25 Feb 2025 14:19 |
| PMCID: | PMC8279504 |
| URI: | https://repository.cshl.edu/id/eprint/40294 |
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