Shugoshin 2A stabilizes heterochromatin complexes to suppress the 2-cell-like state in embryonic stem cells.

Two-cell (2C)-specific transcripts important for maternal zygotic transition, such as Zscan4 and endogenous retrovirus (MERVL), are sporadically expressed in approximately 1%-5% of an embryonic stem cell (ESC) population to maintain ESC and telomere homeostasis. However, the molecular mechanisms regulating the 2-cell-like state in ESCs are not fully understood. Here, we show that Sgo2a is an important suppressor of the 2-cell-like state and telomere length. Loss of Sgo2a reduces the enrichment of heterochromatic H3K9me3 on 2C genes, including Dux, Zscan4 gene clusters and downstream enhancers, resulting in activation of a 2-cell-like state. However, chromosome breakage was detected in Sgo2a-deficient ESCs. Mechanistically, SGO2A promotes the interaction between RIF1 and KAP1, regulates KAP1 ubiquitination, and maintains KAP1 stability at heterochromatin, repressing 2-cell genes. These results reveal a critical role for Sgo2a in suppressing the 2C-like state to maintain the homeostasis and genome stability of ESCs.