造血
干细胞
祖细胞
细胞生物学
移植
生物
调节器
免疫学
癌症研究
医学
内科学
遗传学
基因
作者
Vincenzo Calvanese,Andrew Nguyen,Timothy J. Bolan,Anastasia Vavilina,Trent Su,Lydia K. Lee,Yanling Wang,Fides D. Lay,Mattias Magnusson,Gay M. Crooks,Siavash K. Kurdistani,Hanna Mikkola
出处
期刊:Nature
[Springer Nature]
日期:2019-11-27
卷期号:576 (7786): 281-286
被引量:107
标识
DOI:10.1038/s41586-019-1790-2
摘要
Limited knowledge of the mechanisms that govern the self-renewal of human haematopoietic stem cells (HSCs), and why this fails in culture, have impeded the expansion of HSCs for transplantation1. Here we identify MLLT3 (also known as AF9) as a crucial regulator of HSCs that is highly enriched in human fetal, neonatal and adult HSCs, but downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human haematopoietic stem or progenitor cells (HSPCs) in culture, whereas stabilizing MLLT3 expression in culture enabled more than 12-fold expansion of transplantable HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Similar to endogenous MLLT3, overexpressed MLLT3 localized to active promoters in HSPCs, sustained levels of H3K79me2 and protected the HSC transcriptional program in culture. MLLT3 thus acts as HSC maintenance factor that links histone reader and modifying activities to modulate HSC gene expression, and may provide a promising approach to expand HSCs for transplantation. MLLT3 is identified as a crucial regulator of the self-renewal of human haematopoietic stem cells, and helps to maintain an active chromatin state in haematopoietic stem-cell regulatory genes during culture.
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