DCAF7 regulates hematopoietic stem cell function and differentiation through polycomb repressive complex 1 modulation

Abstract

DCAF7 is one of the few DCAFs expressed in hematopoietic stem cells (HSCs). Using a conditional knockout mouse model, we discovered that the absence of DCAF7 leads to accumulation of differentiating progenitors in the bone marrow, and impairs self-renewal capacity of HSCs upon transplantation. Furthermore, loss of Dcaf7 accelerates the differentiation of HSCs into the myeloid lineage. At the molecular level, DCAF7 interacts with components of the polycomb repressive complex 1 (PRC1) and promotes their assembly into large macromolecular complexes. Chromatin profiling revealed that loss of DCAF7 leads to increased localization of RING1B at transcriptionally active genomic loci. This increased binding was observed at genes involved in myeloid differentiation and was associated with increased mRNA expression. Lastly, inhibition of KDM2/7 proteins rescues the defective growth of Dcaf7 null HSCs in vitro. Together, these data reveal that DCAF7 is a novel regulator of the PRC1 complex and epigenetic enzymes that control HSC differentiation. This study identifies DCAF7 as a new regulator of blood stem cells showing how it controls chromatin to preserve stem cell function with implications for understanding normal and malignant blood formation.