DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation.

Publication Type:

Journal Article


Nat Commun, Volume 12, Issue 1, p.2490 (2021)


Animals, Cell Line, Crystallography, X-Ray, DNA (Cytosine-5-)-Methyltransferase 1, DNA Methylation, Genome, Genomic Instability, Heterochromatin, Histones, Long Interspersed Nucleotide Elements, Mice


<p>DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically &#39;recognizes&#39; H4K20me3 via its first bromo-adjacent-homology domain (DNMT1). Engagement of DNMT1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1&#39;s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.</p>