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

Tu, J., Liu, X., Jia, H., Reilly, J., Yu, S., Cai, C., Liu, F., Lv, Y., Huang, Y., Lu, Z., Han, S., Jiang, T., Shu, X., Wu, X., Tang, Z., Lu, Q., Liu, M.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology   34(9): 11997-12008 (Journal)
Registered Authors
Jia, Haibo, Liu, Mugen
Brg1, Klf2a-NO signaling, chromatin remodeling, epigenetics, hematopoietic stem cells
MeSH Terms
  • Adaptor Proteins, Signal Transducing/genetics
  • Adaptor Proteins, Signal Transducing/metabolism*
  • Animals
  • Embryo, Nonmammalian/embryology*
  • Gene Expression Regulation, Developmental
  • Gene Knockout Techniques
  • Hematopoiesis*
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/metabolism*
  • Kruppel-Like Transcription Factors/biosynthesis
  • Kruppel-Like Transcription Factors/genetics
  • Nitric Oxide/genetics
  • Nitric Oxide/metabolism
  • Response Elements
  • Stem Cell Niche*
  • Transcription, Genetic
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
32738093 Full text @ FASEB J.
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 a brg1 knockout zebrafish model using TALEN technology. We found that in brg1-/- 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 in brg1-/- 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 of KLF2 and trigger its transcriptional activity of NO synthase. Our findings show that Brg1 promotes klf2a expression in hemogenic endothelium and highlight a novel mechanism for HSPC formation and maintenance.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes