The role of HELLS in human induced pluripotent stem cells

DNA methylation is essential for genome integrity and involves multi-layered chromatin interac-tions that require remodeling proteins like the Helicase, Lymphoid-specific (HELLS). Here, we generate HELLS and de novo DNA methyltransferase 3 A and B (DNMT3A/B) knockout human pluripotent stem cells and assemble telomere-to-telomere maps of whole genome bisulfite se-quencing data combined with ATAC-sequencing. Disrupting HELLS induces a global loss of DNA methylation that is distinct from the de novo DNMTs, in particular over peri/centromeric satellite repeats as defined in the telomere-to-telomere genome assembly. However, HELLS is dispen-sable for local enhancer remodeling and the potential to differentiate into the three germ layers. Taken together, these findings further clarify the genomic targets and role of HELLS in human cells. Whole genome bisulfite sequencing was performed on proliferating and G2-arrested WT and HELLS KO iPSCs as well as on HELLS KO iPSC-derived Endoderm cells.