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H3 K27M and EZHIP Impede H3K27-Methylation Spreading by Inhibiting Allosterically Stimulated PRC2.
Jain, Siddhant U; Rashoff, Andrew Q; Krabbenhoft, Samuel D; Hoelper, Dominik; Do, Truman J; Gibson, Tyler J; Lundgren, Stefan M; Bondra, Eliana R; Deshmukh, Shriya; Harutyunyan, Ashot S; Juretic, Nikoleta; Jabado, Nada; Harrison, Melissa M; Lewis, Peter W.
Afiliação
  • Jain SU; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Rashoff AQ; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Krabbenhoft SD; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Hoelper D; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Do TJ; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Gibson TJ; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Lundgren SM; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Bondra ER; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Deshmukh S; Department of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Harutyunyan AS; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
  • Juretic N; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
  • Jabado N; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
  • Harrison MM; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
  • Lewis PW; Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA. Electronic address: peter.lewis@wisc.edu.
Mol Cell ; 80(4): 726-735.e7, 2020 11 19.
Article em En | MEDLINE | ID: mdl-33049227
ABSTRACT
Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP (CXorf67), respectively. H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3 lysine 27 trimethylation (H3K27me3) levels; however, residual peaks of H3K27me3 remain at CpG islands (CGIs) through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with PRC2 that is allosterically activated by H3K27me3 at CGIs and impede its spreading. Moreover, H3 K27M oncohistones reduce H3K27me3 in trans, independent of their incorporation into the chromatin. Although EZHIP is not found outside placental mammals, expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism. Our results provide mechanistic insights for the retention of residual H3K27me3 in tumors driven by H3 K27M and EZHIP.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Histonas / Regulação Neoplásica da Expressão Gênica / Proteínas Oncogênicas / Metilação de DNA / Complexo Repressor Polycomb 2 / Mutação Limite: Animals / Humans Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Histonas / Regulação Neoplásica da Expressão Gênica / Proteínas Oncogênicas / Metilação de DNA / Complexo Repressor Polycomb 2 / Mutação Limite: Animals / Humans Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos