Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome

The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. While mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 co-regulates divergent cell fates remains only partially characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome and Down Syndrome associated acute megakaryoblastic leukemia, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Hence, we hypothesized that chromatin accessibility facilitates lineage specificity of GATA1, thereby permitting efficient cellular differentiation. To understand the connection between chromatin accessibility and GATA1, we performed comprehensive studies of erythropoiesis in Stag2{Delta} mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid maturation, increased number of MkPs, and increased megakaryocytes. RNA- and ATAC-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Gata1 occupancy was lost at erythroid targets, while occupancy increased at megakaryocyte targets. Functionally, we observed that Stag2-deficient EryPs have diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays. Human models and primary MDS patients recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study advances the understanding of the interplay between TF function and chromatin accessibility. Moreover, these data suggest a novel conceptual paradigm of dyserythropoiesis in MDS. Key Pointsxxxxx