Stag2-mediated chromatin dynamics regulates antibody class switch recombination [ChIP-Seq]

Class switch recombination (CSR) in B lymphocytes generates different functional antibody isotypes and cohesin-mediated chromatin loop extrusion is proposed to promote CSR. However, the detailed regulatory mechanism of cohesin in CSR is largely lacking. Here, we revealed that Stag2 is a specific cohesin regulator playing critical roles in promoting CSR. Stag2-deficiency, not Stag1-deficiency, significantly decreases the interaction of acceptor CH with CSR center, leading to decreased transcription of acceptor CH and impaired CSR. Notably, Stag2 could compensate for Stag1 binding within Igh upon Stag1-deficiency, while Stag2-deficiency significantly decreases Stag1 binding within Igh. Interestingly, Stag2 expression is higher than Stag1 during germinal center (GC) B cell development and Stag2 expression has a high correlation with CSR level in GC B cells upon vaccination and SARS-Cov-2 infection. Furthermore, Stag2 is also highly expressed in GC B cells within different tumors, corresponding to the high level of CSR in tumors. Altogether, our findings uncover the unrecognized specific roles of Stag2 in regulating CSR during physiological and pathological immune responses.