The H3K36me2 writer-reader dependency in H3K27M-DIPG

Reinberg, D.; Yu, J.-R.; LeRoy, G.; Bready, D.; Frenster, J. D.; Saldana-Meyer, R.; Jin, Y.; Descostes, N.; Stafford, J. M.; Placantonakis, D. G.

doi:10.1101/2021.01.06.425580

bioRxiv · 10.1101/2021.01.06.425580

The H3K36me2 writer-reader dependency in H3K27M-DIPG

Reinberg, D.·Yu, J.-R.·LeRoy, G.·Bready, D.·Frenster, J. D.·Saldana-Meyer, R.·Jin, Y.·Descostes, N.·Stafford, J. M.·Placantonakis, D. G.

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Abstract

The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, the placement of methylation at lysine 27 of histone H3 (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 in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic 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. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.

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Reinberg, D., Yu, J.-R., LeRoy, G., Bready, D., Frenster, J. D., Saldana-Meyer, R., Jin, Y., Descostes, N., Stafford, J. M., Placantonakis, D. G.. 2021-01-06. The H3K36me2 writer-reader dependency in H3K27M-DIPG. https://doi.org/10.1101/2021.01.06.425580

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