title: Derepression of the DNA Methylation Machinery of theGata1Gene Triggers the Differentiation Cue for Erythropoiesis.
abstract: GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of theGata1gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (theGata1methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of theGata1gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of theGata1gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring aGata1bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressedGata2transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion ofDnmt1in HSPCs activatedGata1expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takai
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Otsuki
authors.affiliation: Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.affiliation: Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Katayama
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nezu
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan masiyamamoto@med.tohoku.ac.jp.|Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004622:Embryo, Mammalian / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006238:Haploidy; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008822:Mice, Transgenic; D008954:Models, Biological; D016019:Survival Analysis
chemical_list: D050982:GATA1 Transcription Factor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C045073:Cre recombinase; D019426:Integrases
keywords: Gata1 gene regulation; erythropoiesis; hematopoietic stem and progenitor cell