title: A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin.
abstract: The readout of histone modifications plays a critical role in chromatin-regulated processes. Dimethylation at Lys-36 on histone H3 (H3K36me2) is associated with actively transcribed genes, and global up-regulation of this modification is associated with several cancers. However, the molecular mechanism by which H3K36me2 is sensed and transduced to downstream biological outcomes remains unclear. Here we identify a PWWP domain within the histone lysine methyltransferase and oncoprotein NSD2 that preferentially binds to nucleosomes containing H3K36me2. In cells, the NSD2 PWWP domain interaction with H3K36me2 plays a role in stabilizing NSD2 at chromatin. Furthermore, NSD2's ability to induce global increases in H3K36me2 via its enzymatic activity, and consequently promote cellular proliferation, is compromised by mutations within the PWWP domain that specifically abrogate H3K36me2-recognition. Together, our results identify a pivotal role for NSD2 binding to its catalytic product in regulating its cellular functions, and suggest a model for how this interaction may facilitate epigenetic spreading and propagation of H3K36me2.
authors.affiliation: From the Department of Biology and.
authors.forename: Saumya M
authors.initials: SM
authors.lastname: Sankaran
authors.affiliation: From the Department of Biology and.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wilkinson
authors.affiliation: Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, California 94305.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Elias
authors.affiliation: From the Department of Biology and ogozani@stanford.edu.
authors.forename: Or
authors.initials: O
authors.lastname: Gozani
mesh_terms: D049109:Cell Proliferation / Q000502:physiology*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human
keywords: chromatin; chromatin modification; chromatin regulation; histone methylation; histone modification