ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation – University of Copenhagen

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29 September 2015

ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation

Knudsen, Kasper Jermiin, Matilda Rehn, Marie Sigurd Hasemann, Nicolas Rapin, Frederik Otzen Bagger, Ewa Ohlsson, Anton Willer, Anne-Katrine Frank, Elisabeth Søndergaard, Johan Jendholm, Lina Thorén, Julie Lee, Justyna Rak, Kim Theilgaard-Mönch & Bo Torben Porse (2015). ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation. Genes & Development, 29(18), 1915-1929, doi:10.1101/gad.268409.115.

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.