| Literature DB >> 31776511 |
Vincenzo Calvanese1,2, Andrew T Nguyen3, Timothy J Bolan3, Anastasia Vavilina3, Trent Su4, Lydia K Lee5, Yanling Wang3, Fides D Lay3, Mattias Magnusson3,6, Gay M Crooks6,7,8, Siavash K Kurdistani6,4,8,9, Hanna K A Mikkola10,11,12,13.
Abstract
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.Entities:
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Year: 2019 PMID： 31776511 PMCID： PMC7278275 DOI： 10.1038/s41586-019-1790-2
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962