Nucleosomes and DNA methylation – implications for immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome and cancers

DNA methylation is a broadly observed epigenetic modification. As genomic DNA methylation profiles dynamically change during development and aging, alterations in DNA methylation patterns are linked to diseases such as cancers and immunodeficiency. ICF syndrome is characterized by hypomethylation at heterochromatin. Of four proteins whose mutation cause ICF syndromes (DNMT3B, ZBTB24, CDCA7 and HELLS), we have previously demonstrated that CDCA7 is a critical activator for the nucleosome remodeling activity of the SNF2-family ATPase HELLS. As DNA methyltransferases cannot directly methylate DNA on the nucleosome, we suggested that the CDCA7-HELLS complex assists DNA methyltransferases by sliding DNA on the nucleosome. However, it remained unclear why the CDCA7-HELLS complex, among several SNF2-family proteins that can remodel nucleosomes, plays a unique role in DNA methylation. Here, I will share our efforts to fill this gap by showing that CDCA7 is an adaptor for hemimethylated CpG. Implications of this finding for diseases will be discussed.