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

## TL;DR

This study shows that SGO2A protein helps maintain genome stability in embryonic stem cells by suppressing genes associated with an early developmental state.

## Contribution

The study identifies SGO2A as a novel regulator of the 2-cell-like state through its role in stabilizing heterochromatin complexes.

## Key findings

- SGO2A promotes H3K9me3 enrichment on 2C genes like Dux and Zscan4 to suppress the 2-cell-like state.
- SGO2A maintains genome stability by regulating KAP1 stability and interaction with RIF1.
- Loss of SGO2A leads to chromosome breakage and activation of a 2-cell-like state in ESCs.

## Abstract

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.

•SGO2A suppresses the 2-cell like genes in mouse embryonic stem cells•SGO2A regulates the enrichment of H3K9me3 on Dux, Zscan4 cluster and downstream enhancer•SGO2A promotes the interaction between RIF1 and KAP1 to maintain the stability of KAP1•SGO2A maintains telomere stability in mouse embryonic stem cells

SGO2A suppresses the 2-cell like genes in mouse embryonic stem cells

SGO2A regulates the enrichment of H3K9me3 on Dux, Zscan4 cluster and downstream enhancer

SGO2A promotes the interaction between RIF1 and KAP1 to maintain the stability of KAP1

SGO2A maintains telomere stability in mouse embryonic stem cells

By regulating the stability of KAP1, SGO2A promotes the enrichment of H3K9me3 on Dux, Zscan4 gene cluster and downstream enhancer to suppress the 2C state in ESCs.