title: The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis.
abstract: Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here, we show that the SET domain, and thus HMT activity of MLL1, is dispensable for maintaining HSCs and supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation is selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 is sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Bibhu P
authors.initials: BP
authors.lastname: Mishra
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Zaffuto
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Artinger
authors.affiliation: Eli and Edythe Broad Center for Stem Cell Research and Regenerative Medicine, Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Tonis
authors.initials: T
authors.lastname: Org
authors.affiliation: Eli and Edythe Broad Center for Stem Cell Research and Regenerative Medicine, Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Hanna K A
authors.initials: HK
authors.lastname: Mikkola
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Institute for Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Proliferation, Université Paul Sabatier-Toulouse III, Bât4R3-B1118 Route de Narbonne, 31062 Toulouse, France.
authors.forename: Malek
authors.initials: M
authors.lastname: Djabali
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Electronic address: patricia.ernst@dartmouth.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D051548:Histone Acetyltransferases; C000622683:Kat8 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1