Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation. [Display omitted] •Hematopoietic Stag2 loss enhances stem cell self-renewal and impairs differentiation•Stag1 can maintain TAD boundary integrity in the absence of Stag2•Stag2 is required for intra-TAD interactions at lineage genes (e.g., PU.1 targets)•Stag2 target expression, but not PU.1 overexpression, restores B cell differentiation In murine hematopoietic Stag2 deletion, Stag1 rescues topologically associated domains in the absence of Stag2 but cannot restore the chromatin architecture required for hematopoietic lineage commitment. PU.1 target genes lose accessibility and expression. Induced target gene expression, but not PU.1 overexpression, is sufficient to restore differentiation in the altered chromatin state.