A multivalent signal-transducing model for the DNMT1-mediated maintenance DNA methylation

Heterochromatin-specific histone modifications frequently coexist with mammalian DNA methylation to orchestrate a repressive chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, we report that the first bromoadjacent homology (BAH1) domain and the replication foci targeting sequence (RFTS) of maintenance DNA methyltransferase DNMT1 function as readers for H4K20me3 and H3K9me3, respectively. Engagements of H4K20me3 by BAH1 and H3K9me3 by RFTS ensure localization of DNMT1 to heterochromatin in cells, and cooperate with the RFTS-ubiquitination readout to allosterically stimulate DNMT1 s methylation activity at both global and focal levels. Strikingly, there is intramolecular crosstalk between the RFTS and BAH1 domains, which profoundly impacts the maintenance of DNA methylation and genomic resistance to radiation damage. Together, our study reveals an all-in-one model for DNMT1 in which repressive histone modifications directly influence the cellular landscape of DNA methylation and genomic stability, a process implicative of the DNMT1-related pathogenesis. Overall design: To examine patterns of maintenance DNA methylation deposited by DNMT1 in cells, we stably transduced either WT or mutant DNMT1 into mouse ES cells with knockout (KO) of DNMT1 (1KO), followed by genome-wide methylation in cells by enhanced reduced representation bisulfite sequencing (eRRBS). eRRBS was carried out side-by-side in three biological replicates of the 1KO rescued lines to generate datasets for across-sample comparisons.