DNMT1 reads heterochromatic H4K20me3 to reinforce DNA methylation of transposons

DNA methylation and trimethylated histone H4K20 (H4K20me3) constitute two important epigenetic mechanisms that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two modifications crosstalk. Here, we report the specific readout of heterochromatin marks H4K20me3 by the first bromo-adjacent-homology (BAH1) domain of maintenance DNA methyltransferase DNMT1. Engagement of BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1, and cooperates with the previously reported readout of H3K9me3/H3 ubiquitination by the RFTS domain to allosterically stimulate DNMT1's activity at both global and focal levels. Interplay between RFTS and BAH1 domains profoundly impacts the maintenance of DNA methylation and genomic resistance to radiation damage. Together, our study provides a heterochromatin-regulated model for DNMT1 in which multivalent recognition of repressive histone modifications by DNMT1 directly influence the cellular landscape of DNA methylation and genomic stability. Overall design: H4K20me3 CUT&RUN was performed in Dnmt1 KO ES cell overexpressed with wild type or W796A DNMT1.