Journal
GENES & DEVELOPMENT
Volume 29, Issue 18, Pages 1915-1929Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.268409.115
Keywords
hematopoietic stem cell; ERG; MYC; differentiation; self-renewal; CPI-203
Categories
Funding
- Danish Cancer Society [A1007, DP08059]
- Lundbeck Foundation [26130, 29367]
- NovoNordisk Foundation [34220]
- NovoNordisk Foundation (The NovoNordisk Foundation Section for Stem Cell Biology in Human Disease)
- Novo Nordisk Foundation [35247]
- Lundbeck Foundation [R108-2012-10312, R9-2007-978] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC1015986, NNF15CC0018344] Funding Source: researchfish
- The Danish Cancer Society [R72-A4572] Funding Source: researchfish
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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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