Abstract
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 ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-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’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.
Highlights
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
This observation was subsequently confirmed by individual peptide pull-down assays, in which GST-tagged hDNMT1728–1600 showed a strong preference for H4K20me[3] and H4K20me[2] over H4K20me[1] and H4K20me[0] (Fig. 1c)
Peptide pull-down and isothermal titration calorimetry (ITC) assays further narrowed down the interaction region to the BAH1 domain (Fig. 1d and Supplementary Fig. 1a and Supplementary Table 1), with preference for H4K20me[3] over other lysine-trimethylated histone peptides (Fig. 1e and Supplementary Fig. 1b)
Summary
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 It remains elusive how these two chromatin modifications crosstalk. Engagement of DNMT1BAH1-H4K20me[3] 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., H3K9me[3] and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Dysregulation of H4K20me[3] and DNA methylation has been associated with neurological and developmental disorders, such as fragile X syndrome[8,9] and Hutchinson–Gilford Progeria Syndrome (HGPS)[10] It remains far from clear how these two gene-repressive epigenetic modifications cooperate in determining specific chromatin states during normal and pathological development. The mechanism by which these or other regulatory elements are coordinated in fine-tuning the activity of DNMT1 at discrete chromatin regions remains poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
