Context-dependent regulation of IgH V(D)J recombination by cohesin-STAG1 and cohesin-STAG2 [ChIP-seq]

Here, we investigate the distinct contributions of two cohesin subunits, STAG1 and STAG2, which are incorporated in the somatic cohesin variants, cohesin-STAG1 and cohesin-STAG2, respectively. Using WAPL-sufficient mouse v-Abl pro-B cells to model the D-to-JH recombination stage, we show that STAG2 promotes balanced D-to-JH joining and restrains STAG1 expression.

Loss of STAG2 elevates cohesin-STAG1 occupancy on chromatin, leading to premature long-range loop formation and expanded VH usage at the expense of distal DH usage. This phenotype persists in the absence of the cohesin acetyltransferase ESCO1 but requires the N-terminal YDF motif of CTCF, which protects cohesin from WAPL-mediated chromatin release. In WAPL-depleted cells modeling the VH-to-DJH recombination stage, the CTCF N-terminus is dispensable and both cohesin variants act cooperatively to establish a diverse VH repertoire.