The chromatin remodeler Brg1 is required for formation and maintenance of hematopoietic stem cells
The chromatin remodeler Brg1 is required for formation and maintenance of hematopoietic stem cells
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染色质重塑蛋白 Brg1 是造血干细胞形成和维持所必需的
DOI：
10.1096/fj.201903168rr
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Liu Mugen
中科院分区：
文献类型：
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作者：
Tu Jiayi;Liu Xiliang;Jia Haibo;Reilly James;Yu Shanshan;Cai Chen;Liu Fei;Lv Yuexia;Huang Yuwen;Lu Zhaojing;Han Shanshan;Jiang Tao;Shu Xinhua;Wu Xiaoyan;Tang Zhaohui;Lu Qunwei;Liu Mugen
造血干细胞和祖细胞（HSPCs）具有自我更新和分化为各种血细胞的能力，因此在维持终身造血中发挥重要作用。Brahma相关基因1（BRG 1）作为哺乳动物SWI-SNF相关染色质重塑复合物的ATP亚基，参与人类急性髓性白血病并在短期HSPC中高度表达。但其在HSPC发展中的作用和调控机制尚未完全确立。本文利用TALEN技术构建了abrg 1基因敲除斑马鱼模型。我们发现，在brg 1 −/−胚胎中，原始造血保持良好，而最终造血形成明显受损。造血内皮细胞数量减少，进一步影响永久性造血，骨髓和淋巴细胞减少。在胚胎发生过程中，brg 1 −/−胚胎中的一氧化氮（NO）微环境受到严重破坏，HSPCs的减少可以通过NO供体部分挽救。染色质免疫沉淀（ChIP）实验表明，BRG 1可以与KLF 2的启动子结合，并激活其NO合成酶的转录活性。我们的研究结果表明Brg 1促进造血内皮细胞中sklf 2a的表达，并强调了HSPC形成和维持的新机制。
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.