Hhex regulates hematopoietic stem cell self-renewal and stress hematopoiesis via repression of Cdkn2a
Details
Publication Year 2017-06-02, Volume 35, Issue #8, Page 1948-1957
Journal Title
Stem Cells
Publication Type
Journal Article
Abstract
The Hematopoietically-expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of Common Lymphoid Progenitors (CLPs) to lymphoid lineages. Here we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin- Sca+ Kit+ (LSK) cells showed that Hhex deletion leads to derepression of Polycomb Repressive Complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink4a and p19Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. This article is protected by copyright. All rights reserved.
Publisher
Wiley
WEHI Research Division(s)
Cancer And Haematology; Bioinformatics
PubMed ID
28577303
Publisher's Version
https://doi.org/10.1002/stem.2648
NHMRC Grants
NHMRC/1003391 NHMRC/1085765
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-08-30 02:21:05
Last Modified: 2018-03-12 01:37:07
An error has occurred. This application may no longer respond until reloaded. Reload 🗙