Roles of meiotic and mitotic cohesin in stem cell gene regulation and genome stability

Abstract

Cohesin, a ring-shaped SMC complex, mediates sister-chromatid cohesion, DNA repair, and genome folding via loop extrusion. Pluripotent and somatic cells were thought to rely solely on mitotic cohesin (SMC1A, SMC3, RAD21, STAG1/STAG2), while meiosis-specific subunits (SMC1B, REC8, STAG3) were considered germline-restricted. This notion has been challenged, as transcriptomic, proteomic, and chromatin-based evidence shows REC8 and STAG3 are expressed in embryonic stem cells (ESCs), assemble with core subunits like SMC3, and occupy genomic sites distinct from canonical RAD21-cohesin. Here, we compare meiotic and mitotic cohesin in subunit composition, expression, regulatory sensitivities, residence times, and removal mechanisms. We examine how each complex regulates enhancer-promoter communication, couples to the rapid pluripotent cell cycle, and how ESC gene-regulatory landscapes differ from differentiated fibroblasts. We extend the principle that cohesin is recruited by active cis-regulatory elements and lineage-determining transcription factors to build cell-type-specific chromatin domains, applying this to meiotic cohesin variants in pluripotent nuclei. Finally, we discuss how REC8/STAG3-containing complexes support replication-fork protection and genome stability during the shortened ESC cell cycle. These findings show that the meiotic-mitotic chromosome organization boundary is permeable, with meiotic cohesin acting as a noncanonical regulator of chromatin architecture and gene expression in pluripotent stem cells.