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: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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Project description:Loss of DNA methylation is a hallmark of cancer that is proposed to promote carcinogenesis through gene expression alterations, retrotransposon activation and induction of genomic instability. Cancer-associated hypomethylation does not occur across the whole genome but leads to the formation of partially methylated domains (PMDs). However, the mechanisms underpinning PMD formation remain unclear. PMDs replicate late in S-phase leading to the proposal that they become hypomethylated due to incomplete re-methylation by the maintenance methyltransferase DNMT1 during cell division. Here we investigate the role of DNMT1 in the formation of PMDs in cancer by conducting whole genome bisulfite sequencing (WGBS), repli-seq and ChIP-seq on DNMT1 knockout HCT116 colorectal cancer cells (DNMT1 KO cells). We find that DNMT1 loss leads to preferential hypomethylation in late replicating, heterochromatic PMDs marked by the constitutive heterochromatic mark H3K9me3 or the facultative heterochromatic mark H3K27me3. However, we also observe that a subset of H3K9me3-marked PMDs gain methylation in DNMT1 KO cells. We find that, in DNMT1 KO cells, these hypermethylated PMDs remain late replicating but gain DNMT3A localisation. This is accompanied by loss of heterochromatic H3K9me3 and specific gain of euchromatic H3K36me2. Our observations suggest that hypermethylated PMDs lose their heterochromatic state, enabling their methylation by DNMT3A and the establishment of a hypermethylated, non-PMD state, despite their late replication timing. More generally, our findings suggest that the de novo DNMTs play a key role in establishing domain level DNA methylation patterns in cancer cells.
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