The H3K36me2 writer-reader dependency in H3K27M-DIPG.
Jia Ray Yu,Jia Ray Yu,Gary LeRoy,Gary LeRoy,Devin Bready,Joshua D. Frenster,Ricardo Saldaña-Meyer,Ricardo Saldaña-Meyer,Ying Jin,Nicolas Descostes,Nicolas Descostes,Nicolas Descostes,James M. Stafford,James M. Stafford,James M. Stafford,Dimitris G. Placantonakis,Danny Reinberg,Danny Reinberg +17 more
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TLDR
In this paper, the role of H3K36me2 in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor, was investigated by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers).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.read more
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Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies.
Izac J. Findlay,Geoffry N. De Iuliis,Ryan J. Duchatel,Evangeline R. Jackson,Nicholas A Vitanza,Nicholas A Vitanza,Jason E. Cain,Jason E. Cain,Sebastian M. Waszak,Matthew D. Dun +9 more
TL;DR: The recent World Health Organization's 5th Classification of CNS Tumors now designates DMG as, ‘H3 K27-altered’, suggesting that global H3K27me3 hypomethylation is a ubiquitous feature of DMG and drives devastating transcriptional programs for which there are no treatments as discussed by the authors.
Journal ArticleDOI
Structural and functional specificity of H3K36 methylation
TL;DR: In this article , structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-, tri-, and tri-(H3K 36me3) methylated forms, have been identified.
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Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation.
TL;DR: In this article , the authors survey this rapidly expanding research field with particular emphasis on how histone mutants, even at low dosage, can corrupt chromatin states, highlighting how studies of oncohistones have leveraged, and in some cases fueled, the advances in our ability to manipulate and interrogate chromatin at the molecular level.
Journal ArticleDOI
Structural and functional specificity of H3K36 methylation
TL;DR: In this article , structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-, tri-, and tri-(H3K 36me3) methylated forms, have been identified.
Journal ArticleDOI
Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4
TL;DR: Panditharatna et al. as discussed by the authors showed that SMARCA4, the catalytic subunit of the mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration, and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models.
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