Arid2 regulates HSC differentiation in normal hematopoiesis

ABSTRACT The Switch/Sugar Non-Fermenting (SWI/SNF) family of chromatin remodeling complexes have been implicated in normal hematopoiesis. The ARID2 protein is a component of the Polybromo-associated BAF (PBAF), one of the two main SWI/SNF complexes. In the current study, we used a conditional Arid2 knockout mouse model to understand its role in normal hematopoiesis. We showed that the loss of Arid2 has no discernable effects on steady state hematopoiesis, with the exception of a modest effect on erythropoiesis. Whereas, upon bone marrow transplantation, the loss of Arid2 affects HSC differentiation in a cell-autonomous manner, resulting in significant decreases in the ability to reconstitute the lymphoid lineage. Gene expression analysis of Arid2 knockout cells showed enrichment of myeloid-biased multipotent progenitor (MPP) cell signatures, while the lymphoid-biased MPP are enriched in the wild type, consistent with the observed phenotype. Moreover, Arid2 knockout cells showed enrichment of inflammatory pathways with up-regulation of TLR receptors, as well as, downstream signaling cascade genes. Furthermore, under lymphocyte biased growth conditions in-vitro, Arid2 null bone marrow cells have significantly impaired proliferation which decreased further upon LPS stimulation. Overall, these data suggest that the loss of Arid2 impairs HSC differentiation ability and this effect may be mediated through up regulation of inflammatory pathways.