SRA

Accumulative studies indicate that DNA maintenance methylation by DNMT1 is initiated by binding of UHRF1 to replication fork. However, how UHRF1 gains access to chromatin in S phase is poorly understood. Here we report that LSH, a SNF2 family chromatin remodeler, facilitates DNA methylation in somatic cells primarily by promoting DNA methylation by DNMT1. We show that knockout of LSH in various somatic cells resulted in substantial reduction of DNA methylation, whereas knockout of DNMT3A and DNMT3B only moderately reduced the level of DNA methylation. Consistent with a role in maintenance methylation, genome-wide analysis of DNA methylation revealed a widespread reduction of DNA methylation in all genomic elements in LSH null cells. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association, UHRF1-catalyzed H3 ubiquitination, and subsequent DNMT1 recruitment to replication fork. Notably, UHRF1 also enhances LSH association with replication fork. Thus, our study identifies LSH as an essential factor for maintenance methylation and provides novel insight into how LSH facilitates maintenance methylation. Overall design: Reduced representation bisulfite sequencing (RRBS) were first carried out for LSH KO/WT cells of HCT116 and HeLa. RNA-seq was carried out for LSH KO/WT cells of HeLa.