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

Area of Science:

• Epigenetics and Gene Regulation
• Chromatin Biology
• Stem Cell Differentiation

Background:

• DNA methylation is vital for cellular function and is regulated by complex chromatin interactions.
• Helicase, lymphoid-specific (HELLS) is a key remodeling protein involved in DNA methylation.
• DNA methyltransferases 3A and B (DNMT3A/B) are essential for establishing DNA methylation patterns.

Purpose of the Study:

• To investigate the specific role of HELLS in DNA methylation regulation within human pluripotent stem cells.
• To compare the effects of HELLS disruption with DNMT3A/B disruption on DNA methylation.
• To elucidate the genomic targets and functions of HELLS in human cells.

Main Methods:

• Generation of HELLS and DNMT3A/B knockout human pluripotent stem cells.
• Telomere-to-telomere whole genome bisulfite sequencing (WGBS) to map DNA methylation.
• ATAC-sequencing to assess chromatin accessibility.

Main Results:

• HELLS disruption led to a global loss of DNA methylation, distinct from DNMT3A/B knockout effects.
• This methylation loss was particularly pronounced at peri/centromeric satellite repeats.
• HELLS was found to be dispensable for local enhancer remodeling and differentiation potential.

Conclusions:

• HELLS plays a critical, distinct role in maintaining DNA methylation, especially at satellite repeats.
• HELLS function in DNA methylation is separate from its role in enhancer regulation and differentiation.
• This study clarifies the specific genomic targets and functions of HELLS in human epigenetics.