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| Status |
Public on May 22, 2017 |
| Title |
Hhex regulates HSC self-renewal and stress hematopoiesis via repression of Cdkn2a |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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. However, whether Hhex plays a role in HSC self-renewal and myeloid expansion during hematopoietic stress is unknown. 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. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature hematopoietic progenitors. Transcriptome analysis of Hhex-null Lin-Sca+Kit+ (LSK) cells showed that Hhex deletion leads to the deregulation of Polycomb Repressive Complex 2 (PRC2) target genes, including an upregulation of Cdkn2a locus, encoding the cell cycle repressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored Hhex-null blast colony replating in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to repress Cdkn2a to enable continued self-renewal and response to hematopoietic stress.
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| Overall design |
Transcriptional profiling of Hhex-deleted and wild-type LSK cells using RNA sequencing
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| Contributor(s) |
Jackson JT, Shields BJ, Shi W, McCormack MP |
| Citation(s) |
28577303 |
| Submission date |
Aug 29, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Wei Shi |
| E-mail(s) |
Wei.Shi@onjcri.org.au
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| Organization name |
Olivia Newton-John Cancer Research Institute
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| Street address |
145 Studley Road
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| City |
Heidelberg |
| State/province |
Victoria |
| ZIP/Postal code |
3084 |
| Country |
Australia |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA340892 |
| SRA |
SRP083323 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE86209_RAW.tar |
650.0 Kb |
(http)(custom) |
TAR (of TXT) |
| GSE86209_Supp_Raw_Counts.txt.gz |
254.0 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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