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

Jiayi Tu, Xiliang Liu, Haibo Jia, James Reilly, Shanshan Yu, Chen Cai, Fei Liu, Yuexia Lv, Yuwen Huang, Zhaojing Lu, Shanshan Han, Tao Jiang, Xinhua Shu, Xiaoyan Wu, Zhaohui Tang, Qunwei Lu, Mugen Liu

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)11997-12008
Number of pages12
JournalFASEB Journal
Volume34
Issue number9
Early online date1 Aug 2020
DOIs
Publication statusPublished - Sep 2020

Keywords

  • Brg1
  • chromatin remodelling
  • epigenetics
  • hematopoietic stem cells
  • Klf2a‐NO signaling

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    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. (2020). The chromatin remodeler Brg1 is required for formation and maintenance of hematopoietic stem cells. FASEB Journal, 34(9), 11997-12008. https://doi.org/10.1096/fj.201903168RR