学术报告

22-05-2022

DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling

报告日期:2022524日,周二下15:00 -16:00

腾讯会议:769-294-165

报告人:王璐,中国医学科学院血液学研究所,研究员

腾讯会议: 769-294-165

摘要: The earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta, through endothelial-to-hematopoietic transition (EHT) during vertebrate embryogenesis. Notch signaling is critical for HSPC generation across vertebrates; however, the precise control of Notch during this process remains unclear. In the present study, we used multi-omics approaches together with functional assays to assess global DNA methylome dynamics during the endothelial cells-to-HSPCs transition in zebrafish, and determined that DNA methyltransferase 1 (Dnmt1) is essential for HSPC generation via repression of Notch signaling. Depletion of dnmt1 resulted in decreased DNA methylation levels and impaired HSPC production. Mechanistically, we found that loss of dnmt1 induced hypomethylation of Notch genes and consequently elevated Notch activity in hemogenic endothelial cells, thereby repressing the generation of HSPCs. This finding deepens our understanding of HSPC specification in vivo, which will provide helpful insights for designing new strategies for HSPC generation in vitro.

个人简介:王璐研究员、博士生导师2013年博士毕业于中国科学院动物研究所,主要利用斑马鱼开展早期胚胎发育的基础研究,尤其是造血干细胞命运决定、维持和分化以及胚胎左右不对称发育等。研究工作涉及造血干细胞产生过程中内源因子、微环境以及表观遗传修饰(RNA甲基化和DNA甲基化)的调控机制,成果包括:发现m6A甲基化调控造血干细胞命运决定(Nature, 2017)以及早期胚胎发育(Cell Res, 2014);揭示DNA甲基化修饰影响左右不对称发育的机制(EMBO J, 2017);转录因子FevBlood, 2013)调控造血干细胞产生且标识胚胎起源的白血病(Leukemia, 2017);阐明炎性信号(Blood, 2015)、血液流动(Blood, 2011)及5羟色胺(JEM, 2017)调控造血干细胞命运决定、维持及存活的分子机制。目前实验室的研究方向为利用模式动物及疾病模型,研究表观遗传修饰在造血干细胞发育调控以及白血病演变中的作用和机制,并以体内理论为指导,初步探索白血病靶向治疗的新策略。

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