title: Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation.
abstract: The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a, an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA Macau Institute for Applied Research in Medicine and Health, State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 519020, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Pathology, and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Schulz
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Changwang
authors.initials: C
authors.lastname: Deng
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Betsabeh K
authors.initials: BK
authors.lastname: Tusi
authors.affiliation: Public Health Studies, The Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Stees
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA Genetics Institute, University of Florida, Gainesville, FL 32610, USA UF health Cancer center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Steiner
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA Genetics Institute, University of Florida, Gainesville, FL 32610, USA UF health Cancer center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Systems Biology Center, NHLBI, National Institute of Health, Bethesda, MD 20814, USA.
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA Genetics Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bungert
authors.affiliation: Department of Pediatrics, Pathology, and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA Patrick.gallagher@yale.edu.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA Macau Institute for Applied Research in Medicine and Health, State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 519020, China Genetics Institute, University of Florida, Gainesville, FL 32610, USA UF health Cancer center, University of Florida College of Medicine, Gainesville, FL 32610, USA sumingh@ufl.edu.
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006454:Hemoglobins / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008836:Micrococcal Nuclease / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D034961:Antigens, Nuclear; D002843:Chromatin; D006454:Hemoglobins; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; D008836:Micrococcal Nuclease; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; C497181:USF1 protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins; C110219:Nsccn1 protein, mouse; C526068:Setd1A protein, human