The cohesin regulator Stag1 promotes cell plasticity through heterochromatin regulation

Fundamental biological processes such as embryo development and stem cell control rely on cellular plasticity. We present a role for the cohesin regulator, Stag1 in cellular plasticity control via heterochromatin regulation. Stag1 localises to heterochromatin domains and repetitive sequences in embryonic stem (ES) cells and contains intrinsically disordered regions in its divergent terminal ends which promote heterochromatin compaction. ES cells express Stag1 protein isoforms lacking the disordered ends and fluctuations in isoform abundance skews the cell state continuum towards increased differentiation or reprogramming. The role for Stag1 in heterochromatin condensates and nucleolar function is dependent on its unique N-terminus. Stag1N{Delta} ESCs have decompacted chromatin and reprogram towards totipotency, exhibiting MERVL derepression, reduced nucleolar transcription and decreased translation. Our results move beyond protein-coding gene regulation via chromatin loops into a new role for Stag1 in heterochromatin and nucleolar function and offer fresh perspectives on its contribution to cell identity and disease.