ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation
- Kasper Jermiin Knudsen1,2,3,7,
- Matilda Rehn1,2,3,7,
- Marie Sigurd Hasemann1,2,3,
- Nicolas Rapin1,2,3,4,
- Frederik Otzen Bagger1,2,3,4,
- Ewa Ohlsson1,2,3,
- Anton Willer1,2,3,
- Anne-Katrine Frank1,2,3,
- Elisabeth Søndergaard1,2,3,
- Johan Jendholm1,2,3,
- Lina Thorén1,2,3,
- Julie Lee1,2,3,
- Justyna Rak5,
- Kim Theilgaard-Mönch1,2,6,8 and
- Bo Torben Porse1,2,3,8
- 1The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
- 2Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark;
- 3Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
- 4The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
- 5Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, SE-22184 Lund, Sweden;
- 6Department of Hematology, Skånes University Hospital, University of Lund, SE-22185 Lund, Sweden
- Corresponding author: bo.porse{at}finsenlab.dk
Abstract
The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.268409.115.
- Received July 7, 2015.
- Accepted August 27, 2015.
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