title: SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPɛ dependent mechanism.
abstract: Recent studies suggest that individual subunits of chromatin-remodeling complexes produce biologically specific meaning in different cell types through combinatorial assembly. Here we show that granulocyte development requires SMARCD2, a subunit of ATP-dependent SWI/SNF (BAF) chromatin-remodeling complexes. Smarcd2-deficient mice fail to generate functionally mature neutrophils and eosinophils, a phenotype reminiscent of neutrophil-specific granule deficiency (SGD) in humans, for which loss-of-function mutations in CEBPE (encoding CEBPɛ) have been reported. SMARCD2-containing SWI/SNF complexes are necessary for CEBPɛ transcription factor recruitment to the promoter of neutrophilic secondary granule genes and for granulocyte differentiation. The homologous SMARCD1 protein (63% identical at the amino acid level) cannot replace the role of SMARCD2 in granulocyte development. We find that SMARCD2 functional specificity is conferred by its divergent coiled-coil 1 and SWIB domains. Strikingly, both CEBPE and SMARCD2 loss-of-function mutations identified in patients with SGD abolish the interaction with SWI/SNF and thereby secondary granule gene expression, thus providing a molecular basis for this disease.
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.|Department of Pathology and Cellular Biology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Priam
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.|Department of Pathology and Cellular Biology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Veneta
authors.initials: V
authors.lastname: Krasteva
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousseau
authors.affiliation: Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
authors.forename: Giovanni
authors.initials: G
authors.lastname: D'Angelo
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.|Department of Pathology and Cellular Biology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Gaboury
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.|Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.|Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.|Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.|Department of Pathology and Cellular Biology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lessard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C489468:Cebpe protein, mouse; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D009124:Muscle Proteins; C491651:SMARCD2 protein, human; C494056:Smarcd2 protein, mouse; D014157:Transcription Factors; C070790:CEBPE protein, human