title: The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation.
abstract: Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation, and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes resulted from a cell-intrinsic requirement for Mysm1 in the BM. Importantly, Mysm1(tm1a/tm1a) HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors. Overall, these data establish a role for Mysm1 in the maintenance of BM stem cell function, in the control of oxidative stress and genetic stability in hematopoietic progenitors, and in the development of lymphoid and erythroid lineages.
authors.affiliation: Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Cambridge, United Kingdom. anastasiya.nyzhnyk@mcgill.ca
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Christine
authors.initials: C
authors.lastname: Hale
authors.forename: Claire
authors.initials: C
authors.lastname: Raisen
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: McIntyre
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yusa
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Everitt
authors.forename: Lynda
authors.initials: L
authors.lastname: Mottram
authors.forename: Christine
authors.initials: C
authors.lastname: Podrini
authors.forename: Mark
authors.initials: M
authors.lastname: Lucas
authors.forename: Jeanne
authors.initials: J
authors.lastname: Estabel
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.forename: Niels
authors.initials: N
authors.lastname: Adams
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.forename: Jacqui K
authors.initials: JK
authors.lastname: White
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases
chemical_list: D006657:Histones; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D010450:Endopeptidases; C570173:MYSM1 protein, mouse; D064570:Ubiquitin-Specific Proteases