DNA methylation regulation involves multi-layered chromatin interactions that require remodeling proteins like the helicase, lymphoid-specific (HELLS). Here, we generate HELLS and DNA methyltransferase 3A and B (DNMT3A/B) knockout human pluripotent stem cells and report telomere-to-telomere maps of whole genome bisulfite sequencing data combined with ATAC-sequencing. Disrupting HELLS induces a global loss of DNA methylation that is distinct from the DNMTs, in particular over peri/centromeric satellite repeats as defined in the telomere-to-telomere genome assembly. However, HELLS appears dispensable for local enhancer remodeling and the potential to differentiate into the three embryonic germ layers. Taken together, our results further clarify the genomic targets and role of HELLS in human cells.
