The chromatin remodeler Brg1 is required for formation and maintenance of hematopoietic stem cells

Hematopoietic stem and progenitor cells (HSPCs) have the ability to self-renew and differentiate into various blood cells, thus playing an important role in maintenance of lifelong hematopoiesis. Brahma-related gene 1 (BRG1), which acts as the ATP subunit of mammalian SWI-SNF-related chromatin remodeling complexes, is involved in human acute myeloid leukemia and highly expresses in short-term HSPCs. But its role and regulatory mechanism for HSPC development have not yet been well established. Here, we generated abrg1knockout zebrafish model using TALEN technology. We found that inbrg1(-/-)embryo, the primitive hematopoiesis remained well, while definitive hematopoiesis formation was significantly impaired. The number of hemogenic endothelial cells was decreased, further affecting definitive hematopoiesis with reduced myeloid and lymphoid cells. During embryogenesis, the nitric oxide (NO) microenvironment inbrg1(-/-)embryo was seriously damaged and the reduction of HSPCs could be partially rescued by a NO donor. Chromatin immunoprecipitation (ChIP) assays showed that BRG1 could bind to the promoter ofKLF2and trigger its transcriptional activity of NO synthase. Our findings show that Brg1 promotesklf2aexpression in hemogenic endothelium and highlight a novel mechanism for HSPC formation and maintenance.