Structure of DNMT1-nucleosome complexes reveals a basis for maintenance DNA methylation and regulation in CpG islands [RNA-seq]

ABSTRACT: DNA methylation is an important epigenetic mechanism that is essential for genomic stability and gene regulation. In mammals, DNA methyltransferase DNMT1 plays a critical role in maintaining the DNA methylation landscape during development. However, how DNMT1 interplays with various chromatin environments to shape the DNA methylation landscape across the genome remains unclear. Here we report the structure and regulation of DNMT1-mediated DNA methylation at the nucleosome level. Two clusters of previously underappreciated DNA-binding sites of DNMT1 engage in orthogonal nucleosomal contacts, in concert with the interaction between the DNMT1 RFTS domain and histone H3 carrying dual mono-ubiquitin, underpin DNMT1-mediated maintenance DNA methylation along the nucleosome core particle (NCP)-proximal linker. The interaction of DNMT1 CXXC domain with an unmodified CpG site leads to an autoinhibitory conformation of DNMT1 during the encounter stage, and further allosterically inhibits DNMT1-mediated maintenance DNA methylation at the stage of productive methylation. Introducing a DNMT1 mutation defective in the CXXC-CpG interaction substantially increased the DNA methylation of CpG islands (CGIs) without impacting the overall genomic methylation appreciably, suggesting a CXXC domain-dependent rheostat mechanism restricting DNA methylation in the CGIs associated with vertebrate genomes. Together, this study provides insight into the interplay between the conformational dynamics of DNMT1 and the chromatin environment-guided DNA methylation.

ORGANISM(S): Mus musculus

PROVIDER: GSE338522 | GEO | 2026/08/28

REPOSITORIES: GEO