title: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.
abstract: The histone lysine methyltransferase NSD2 (MMSET/WHSC1) is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here, we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation upon t(4;14)-negative cells and promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together, our findings establish H3K36me2 as the primary product generated by NSD2 and demonstrate that genomic disorganization of this canonical chromatin mark by NSD2 initiates oncogenic programming.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Kuo
authors.forename: Peggie
authors.initials: P
authors.lastname: Cheung
authors.forename: Kaifu
authors.initials: K
authors.lastname: Chen
authors.forename: Barry M
authors.initials: BM
authors.lastname: Zee
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Josh
authors.initials: J
authors.lastname: Lauring
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Or
authors.initials: O
authors.lastname: Gozani
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002843:Chromatin; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D002843:Chromatin; D006657:Histones; D011994:Recombinant Proteins; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D008239:Lysine
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: PLoS One. 2009 Aug 26;4(8):e6789
references.pmid: 19956676
references.citation: Mol Cell Biol. 2008 Mar;28(6):2023-34
references.pmid: 18172012
references.citation: Curr Biol. 2011 Jan 11;21(1):53-8
references.pmid: 21167713
references.citation: Blood. 1998 Nov 1;92(9):3025-34
references.pmid: 9787135
references.citation: Best Pract Res Clin Haematol. 2007 Dec;20(4):571-96
references.pmid: 18070707
references.citation: Clin Immunol. 2008 May;127(2):176-87
references.pmid: 18337172
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):1025-1040
references.pmid: 17984965
references.citation: Mol Cell Biol. 2003 Jun;23(12):4207-18
references.pmid: 12773564
references.citation: Methods Mol Biol. 2003;224:111-36
references.pmid: 12710670
references.citation: Nature. 2010 Jan 21;463(7279):360-3
references.pmid: 20054297
references.citation: Annu Rev Pathol. 2011;6:249-74
references.pmid: 21261519
references.citation: Nature. 2009 Jul 9;460(7252):287-91
references.pmid: 19483677
references.citation: Genome Biol. 2005;6(8):227
references.pmid: 16086857
references.citation: J Biol Chem. 2005 May 6;280(18):17732-6
references.pmid: 15760899
references.citation: Nature. 1983 Aug 18-24;304(5927):596-602
references.pmid: 6308472
references.citation: Blood. 2003 Mar 15;101(6):2374-6
references.pmid: 12433679
references.citation: Nat Struct Mol Biol. 2011 Jan;18(1):91-3
references.pmid: 21131980
references.citation: Cancer Res. 2010 Jun 1;70(11):4287-91
references.pmid: 20501857
references.citation: Nature. 2011 Feb 3;470(7332):124-8
references.pmid: 21293379
references.citation: EMBO J. 2008 Jan 23;27(2):406-20
references.pmid: 18157086
references.citation: Hum Mol Genet. 1998 Jul;7(7):1071-82
references.pmid: 9618163
references.citation: J Biol Chem. 2009 Dec 4;284(49):34283-95
references.pmid: 19808676
references.citation: Blood. 2011 Jan 6;117(1):211-20
references.pmid: 20974671
references.citation: Blood. 2008 Jan 15;111(2):856-64
references.pmid: 17942756
references.citation: Blood. 2003 Feb 15;101(4):1520-9
references.pmid: 12393535
references.citation: Mol Cell Biol. 2005 Apr;25(8):3305-16
references.pmid: 15798214
references.citation: N Engl J Med. 2011 Mar 17;364(11):1046-60
references.pmid: 21410373
references.citation: Blood. 2008 Mar 15;111(6):3145-54
references.pmid: 18156491
references.citation: EMBO J. 2007 Dec 12;26(24):4974-84
references.pmid: 18007591