title: Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement.
abstract: SETD1A is a member of trithorax-related histone methyltransferases that methylate lysine 4 at histone H3 (H3K4). We showed previously that Setd1a is required for mesoderm specification and hematopoietic lineage differentiation in vitro. However, it remains unknown whether or not Setd1a controls specific hematopoietic lineage commitment and differentiation during animal development. Here, we reported that homozygous Setd1a knockout (KO) mice are embryonic lethal. Loss of the Setd1a gene in the hematopoietic compartment resulted in a blockage of the progenitor B-cell-to-precursor B-cell development in bone marrow (BM) and B-cell maturation in spleen. The Setd1a-cKO (conditional knockout) mice exhibited an enlarged spleen with disrupted spleen architecture and leukocytopenia. Mechanistically, Setd1a deficiency in BM reduced the levels of H3K4me3 at critical B-cell gene loci, including Pax5 and Rag1/2, which are critical for the IgH (Ig heavy-chain) locus contractions and rearrangement. Subsequently, the differential long-range looped interactions of the enhancer Eμ with proximal 5' DH region and 3' regulatory regions as well as with Pax5-activated intergenic repeat elements and 5' distal VH genes were compromised by the Setd1a-cKO. Together, our findings revealed a critical role of Setd1a and its mediated epigenetic modifications in regulating the IgH rearrangement and B-cell development.
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Betsabeh Khoramian
authors.initials: BK
authors.lastname: Tusi
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Changwang
authors.initials: C
authors.lastname: Deng
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Tal
authors.initials: T
authors.lastname: Salz
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Leilani
authors.initials: L
authors.lastname: Zeumer
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Yangqiu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Morel
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom qiuy@ufl.edu sumingh@ufl.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Departments of *Biochemistry & Molecular Biology, Pathology, Immunology & Laboratory Medicine, and Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida, USA; Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou, China; and Department of Haematological Medicine, King's College London, London, United Kingdom qiuy@ufl.edu sumingh@ufl.edu.
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019891:Leukopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051757:PAX5 Transcription Factor / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D018398:Homeodomain Proteins; D007473:Ion Channels; D051757:PAX5 Transcription Factor; C110219:Nsccn1 protein, mouse; C497282:Pax5 protein, mouse; C499308:Rag2 protein, mouse; C064658:RAG-1 protein
keywords: B-cell differentiation; Setd1a KO mice; long-range chromatin loops; promoter H3K4me3; transcriptional regulation