DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

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.

Factors Regulating the Activity of LINE1 Retrotransposons

“…The activity of the HUSH complex in humans contributes to the repression of old families of L1P and L1M retrotransposons in the introns of active genes [111]. DNA methylation and histone methylation are interrelated, thus, recently it was found that DNMT1 recognizes heterochromatin markers H3K9me3 and H4K20me3, which profoundly impacts DNA methylation [252,253]. A low level of expression in the mammalian embryonic and adult brains is observed for PIWI family proteins.…”

DNA Double-Strand Break Repair: All Roads Lead to HeterochROMAtin Marks

“…Interestingly, DSB repair alters DNA methylation patterns ( Sriraman et al, 2020 ), but little is known about the mechanisms allowing DNA methylation restoration. Furthermore, the DNA methyltransferase DNMT1 can read heterochromatin histone marks thus protecting cells against ionizing radiation ( Ren et al, 2020 , 2021 ). These findings suggest a potential role for DNA methylation in controlling DSB repair responses, which is still to be elucidated.…”

Retrotransposons as a Source of DNA Damage in Neurodegeneration

“…Repression at the epigenetic level is mostly accomplished by the addition of repressive histone marks, mainly trimethylation of lysine 9 of histone H3 (H3K9me3) (Bulut-Karslioglu et al, 2014;Liu et al, 2014;He et al, 2019), trimethylation of lysine 20 of histone H4 (H4K20me3) (Ren et al, 2021), and histone H1 on LINE-1 loci (Healton et al, 2020), and by DNA methylation (Hata and Sakaki, 1997;Muotri et al, 2010). This is mediated by several sequence-specific repressors that directly bind to TEs and recruit epigenetic modulators.…”

“…These repressive mechanisms include regulation at the epigenetic level by the binding of epigenetic modifiers to the LINE-1 sequence, at the transcriptional level by sequence-specific repressive transcription factors binding to the LINE-1 promoter in the 5′UTR (5′ untranslated region), at the post-transcriptional level by degradation mechanisms (splicing, RNA interference or RNAi, autophagy, and stress granules), at the translational level via RNA binding proteins, at the level of the nuclear import of the RNA, and at the integration level by several factors belonging to the DNA repair machinery ( Pizarro and Cristofari, 2016 ). Repression at the epigenetic level is mostly accomplished by the addition of repressive histone marks, mainly trimethylation of lysine 9 of histone H3 (H3K9me3) ( Bulut-Karslioglu et al, 2014 ; Liu et al, 2014 ; He et al, 2019 ), trimethylation of lysine 20 of histone H4 (H4K20me3) ( Ren et al, 2021 ), and histone H1 on LINE-1 loci ( Healton et al, 2020 ), and by DNA methylation ( Hata and Sakaki, 1997 ; Muotri et al, 2010 ). This is mediated by several sequence-specific repressors that directly bind to TEs and recruit epigenetic modulators.…”