DNA methylation plays a critical role in development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical maintenance enzyme Dnmt1 and the de novo Dnmts, 3a and 3b. Here we demonstrate that in mouse embryonic stem cells, Dnmt1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore sequencing in genetically engineered methylation depleted embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that Dnmt1's de novo methylation activity depends on Uhrf1 and its genomic recruitment overlaps with targets that enrich for Uhrf1, Trim28, and H3K9 trimethylation. Our data demonstrate that Dnmt1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development.
This repository contains the collection of R scripts used to perform the analysis presented in Haggerty and Kretzmer et al. The respository is organized in the following subfolders following the content of the publication.
Source Data files containing the data behind the visualizations are either uploaded as Supplementary Tables or are deposited at https://oc-molgen.gnz.mpg.de/owncloud/s/L2ny9JHey232LAe.
All ChIP and WGBS datasets can be found in the Gene Expression Omnibus (GEO) under accession code GSE158460.