# HELLS is required for maintaining proper DNA modification at human satellite repeats

## TL;DR

This study shows that HELLS is essential for maintaining DNA methylation at satellite repeats in human stem cells.

## Contribution

The paper reveals HELLS's unique role in DNA methylation at satellite repeats, distinct from DNMTs.

## Key findings

- HELLS disruption causes global DNA methylation loss, especially at peri/centromeric satellite repeats.
- Unlike DNMTs, HELLS is not required for enhancer remodeling or germ layer differentiation.
- Telomere-to-telomere genome assembly highlights HELLS's specific genomic targets.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s13059-025-03681-9.