Region-specific generation and retention of acetylated cohesin shape the genome-wide pattern of sister chromatid cohesion

Abstract Sister chromatid cohesion depends on ESCO2-mediated acetylation of the cohesin subunit SMC3, yet how this modification is established and maintained across the genome remains poorly understood. Here, we examined the chromatin-binding dynamics of ESCO2 and its enzymatic activity using quantitative ChIP-seq of human cells synchronously progressing through S phase. ESCO2 bound broadly along chromosomes without forming discrete peaks and preferentially localized to transcriptionally inactive regions, but was not confined to H3K9me3-or H3K27me3-enriched heterochromatin. Consistent with this binding pattern, ESCO2-dependent SMC3 acetylation showed a similarly broad distribution in these regions. In contrast, ESCO1, a paralog of ESCO2, primarily mediated SMC3 acetylation at cohesin peak sites. Notably, most of the broadly distributed, ESCO2-dependent SMC3 acetylation generated during S phase was progressively lost from chromatin after replication, whereas the fraction that persisted into late G2 accumulated in domains enriched for the repressive H3K27me3 modification. Our work identifies selective post-replicative retention of acetylated cohesin as a previously unappreciated step in shaping the genome-wide architecture of sister chromatid cohesion.