DNMT1 reads heterochromatic H4K20me3 to reinforce DNA methylation of transposons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA680755 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13141928_1.fastq.gz | Fastqsanger.gz | |||
| SRR13141928_2.fastq.gz | Fastqsanger.gz | |||
| SRR13141929_1.fastq.gz | Fastqsanger.gz | |||
| SRR13141929_2.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description: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.
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Project description: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.
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