Project description: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, displacement of methylation at lysine 27 of histone H3 (H3K27me2/3), and thus 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.

2021-07-21 | GSE174006 | GEO

Next Generation Sequencing of Two H3K36 methyltransferases during growth mycelia in the Magnaporthe oryzae

Project description:Di- and tri-methylation of lysine 36 on histone H3 (H3K36me2/3) are catalyzed by SET2 histone methyltransferase which play an important role in transcriptional elongation.we reveal a novel mechanism by which H3K36me2 and H3K36me3 associates with opposite transcriptional activity and Ash1 is required for the normal distribution of facultative heterochromatic modifications and stable maintenance of transcriptional silencing in eukaryotes.

2023-11-29 | GSE235261 | GEO

Genome-wide mapping of Two H3K36 methyltransferases during growth mycelia in the Magnaporthe oryzae

2023-11-29 | GSE235260 | GEO