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

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.

The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression

“…Hematopoiesis-specific deletion of BAF subunits affects HSC survival and differentiation (7)(8)(9)(10)(71)(72)(73)(74). For example, the BAF subunit SMARCD2 is required for granulocytic differentiation, and Smarcd2-deficient mice develop macrophage infiltration in the lungs, without an increase in serum levels of proinflammatory cytokines, excluding the possibility of systemic inflammation (75).…”

Role of ATP-dependent chromatin remodelers in hematopoietic stem and progenitor cell maintenance

“…In a zebrafish model, brg1 promotes klf2a expression in hemogenic endothelium and is required for HSPC formation and maintenance. The number of hemogenic endothelial cells in brgl knockout embryos is decreased, affecting subsequent definitive hematopoiesis with reduced myeloid and lymphoid cells [62]. Brm plays a role in HSPC self-renewal, proliferation, and fate decisions by regulating intracellular valine content of the progenitors, which in turn affects self-renewal and possibly differentiation toward progenitors of hematopoietic stem cells [63 && ].…”

The transcriptional regulation of normal and malignant blood cell development

“…During the assembly process, TF complexes recruit further cofactors such as histone acetyltransferases (HATs) that facilitate transcription by modifying the N‐terminal tails of the surrounding nucleosomes and stabilize an open chromatin structure that is devoid of nucleosomes and exists as a nuclease hypersensitive site [63]. Given the importance of chromatin remodelers and modifiers in gene activation, it does not come as a surprise that these proteins are essential components of the regulatory machinery driving hematopoiesis [64–66].…”