High‐resolution Epigenome Mapping Reveals Distinct and Divergent Roles for UHRF1 in the Maintenance of DNA Methylation

Abstract

The E3 ubiquitin ligase UHRF1 is an established cofactor for replication‐coupled DNA methylation inheritance. Our group and others have made recent progress dissecting biochemical mechanisms linking UHRF1 to DNA methylation control. Our current model posits a step‐wise pathway in which UHRF1 engages nucleosomes through histone and DNA binding. This multivalent nucleosome readout directs UHRF1 ubiquitin ligase activity toward the N‐terminal tail of histone H3, a binding site for DNMT1. While this elegant chromatin regulatory process is now taking shape, it remains unclear whether the reliance on UHRF1 for DNA methylation maintenance is localized or genome‐wide. Here we present comparative, high‐resolution, genome‐scale analysis of DNA methylation maintenance following acute depletion of UHRF1 and DNMT1 in a human colorectal cancer cell line. As expected, DNMT1 depletion resulted in global reduction of DNA methylation genome‐wide. However, depletion of UHRF1 revealed distinct attributes of the genome that rely on UHRF1 for DNA methylation maintenance. Significantly, these distinct genomic attributes are divergent on their dependency of ubiquitin deposition on the histone H3 tail by UHRF1 to recruit DNMT1 and maintain DNA methylation. Notably, these newly identified UHRF1‐ubiquitin dependent DNA methylation signatures are consistent with the observed loss of DNA methylation that occurs during aging and cancer progression. We propose that UHRF1 misregulation is a key contributor to DNA methylation erosion that occurs through human lifespan and cancer.Support or Funding InformationThis work was supported by the Van Andel Institute, and grants from the National Institutes of Health to S.B.R. (R35GM124736) and the American Cancer Society ‐ Michigan Cancer Research Fund to R.L.T. (PF‐16‐245‐01‐DMC).