TY - JOUR T1 - The H3K36me2 writer-reader dependency in H3K27M-DIPG JF - bioRxiv DO - 10.1101/2021.01.06.425580 SP - 2021.01.06.425580 AU - Jia-Ray Yu AU - Gary LeRoy AU - Devin Bready AU - Joshua D. Frenster AU - Ricardo SaldaƱa-Meyer AU - Ying Jin AU - Nicolas Descostes AU - James M. Stafford AU - Dimitris G. Placantonakis AU - Danny Reinberg Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/06/2021.01.06.425580.1.abstract N2 - 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.Competing Interest StatementD.R. is a cofounder of Constellation Biotechnology and Fulcrum Biotechnology. D.G.P. and NYU Grossman School of Medicine own a patent in the European Union titled [Method for treating high grade glioma] on the use of GPR133 as a treatment target in glioma. D.G.P. has received consultant fees from Tocagen, Synaptive Medical, Monteris and Robeaute. ER -