DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity

Du, Qiyun; Smith, Grady C.; Luu, Phuc-Loi; Ferguson, James M.; Armstrong, Nicola J.; Caldon, C. Elizabeth; Campbell, E.; Nair, Shalima S.; Zotenko, Elena; Gould, Cathryn M.; Buckley, Michael; Chia, Karin K.M.; Portman, Neil; Lim, Elgene; Kaczorowski, Dominik C.; Chan, Chia-Ling; Barton, Kirston; Deveson, Ira W.; Smith, Martin A.; Powell, Joseph E.; Skvortsova, Ksenia; Stirzaker, Clare; Achinger-Kawecka, Joanna; Clark, Susan J.

doi:10.1016/j.celrep.2021.109722

Cited by 43 publications

(38 citation statements)

References 118 publications

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“…DNA methylation loss occurs primarily within PMDs, which largely coincide with late replication timing domains 8,9 , are enriched in higher order chromatin compartment B 10 , and tend to be associated with the nuclear lamina 7 . Cancer-associated DNA methylation loss is accompanied by changes in replication timing and 3D genome organization 11 . Replicative senescence alters 3D genome compartmentalization 12–14 .…”

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confidence: 99%

Cell division drives DNA methylation loss in late-replicating domains in primary human cells

Endicott

Nolte

Shen

et al. 2022

Preprint

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DNA methylation undergoes dramatic age-related changes, first described more than four decades ago. Loss of DNA methylation at late-replicating regions of the genome attached to the nuclear lamina advances with age in normal tissues, and is further exacerbated in cancer. We present here the first experimental evidence that this DNA hypomethylation is directly driven by proliferation-associated DNA replication. Loss of DNA methylation at low-density CpGs in A:T-rich, partially methylated domains (PMD solo-WCGWs), tracks cumulative population doublings in primary cell culture. Cell cycle deceleration resulted in a proportional decrease in the rate of DNA hypomethylation. Blocking DNA replication via Mitomycin C treatment halted methylation loss. Loss of methylation continued unabated after TERT immortalization until finally reaching a severely hypomethylated equilibrium. Ambient oxygen culture conditions increased the rate of methylation loss compared to low-oxygen conditions, suggesting that some methylation loss may occur during unscheduled, oxidative damage repair-associated DNA synthesis. Finally, we present and validate a model to estimate the relative cumulative replicative histories of human cells, which we call "RepliTali" (Replication Times Accumulated in Lifetime).

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confidence: 99%

Cell division drives DNA methylation loss in late-replicating domains in primary human cells

Endicott

Nolte

Shen

et al. 2022

Preprint

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“…Interestingly, DNA methylation was found to intrinsically modulate chromatin structure and function by increasing chromatin condensation in peri-centromeric regions, decreasing the overall DNA flexibility, and favoring the heterochromatin state [ 122 ]. Further, it has been shown that cancer-related methylation loss is associated with the deregulation of 3D genome organization leading to the disruption of the genome compartmentalization [ 123 ]. DNA methylation can also inactivate TAD boundaries leading to the concomitant activation of key cancer drivers by enhancers located outside their normal TADs through long-range chromatin interactions [ 124 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the effects of genetic variation on gene regulation in cancer in the context of 3D genome structure

2022

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Background Numerous genome-wide association studies (GWAS) conducted to date revealed genetic variants associated with various diseases, including breast and prostate cancers. Despite the availability of these large-scale data, relatively few variants have been functionally characterized, mainly because the majority of single-nucleotide polymorphisms (SNPs) map to the non-coding regions of the human genome. The functional characterization of these non-coding variants and the identification of their target genes remain challenging. Results In this communication, we explore the potential functional mechanisms of non-coding SNPs by integrating GWAS with the high-resolution chromosome conformation capture (Hi-C) data for breast and prostate cancers. We show that more genetic variants map to regulatory elements through the 3D genome structure than the 1D linear genome lacking physical chromatin interactions. Importantly, the association of enhancers, transcription factors, and their target genes with breast and prostate cancers tends to be higher when these regulatory elements are mapped to high-risk SNPs through spatial interactions compared to simply using a linear proximity. Finally, we demonstrate that topologically associating domains (TADs) carrying high-risk SNPs also contain gene regulatory elements whose association with cancer is generally higher than those belonging to control TADs containing no high-risk variants. Conclusions Our results suggest that many SNPs may contribute to the cancer development by affecting the expression of certain tumor-related genes through long-range chromatin interactions with gene regulatory elements. Integrating large-scale genetic datasets with the 3D genome structure offers an attractive and unique approach to systematically investigate the functional mechanisms of genetic variants in disease risk and progression.

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“…S4B), suggesting that DNMT3B may exert its catalytic activity at target regions through long-range interactions. Three-dimensional chromatin structure and DNA methylation are implicated in multiple developmental processes [57], but the precise role of DNMT3B in these processes is not fully characterized. Recent observations suggest that in stem and progenitor cells long loops connecting even dozens of mega bases apart may be anchored in large DNA methylation “grand canyons” [58].…”

Section: Discussionmentioning

confidence: 99%

The rescue of epigenomic abnormalities in ICF1 patient iPSCs following DNMT3B correction is incomplete at a residual fraction of H3K4me3-enriched regions

Krishnan

Morone

Toubiana

et al. 2022

Preprint

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BackgroundBi-allelic hypomorphic mutations in DNMT3B disrupt DNA methyltransferase activity and lead to Immunodeficiency, Centromeric instability, Facial anomalies syndrome, type 1 (ICF1). While several ICF1 phenotypes have been linked to abnormally hypomethylated repetitive regions, the unique genomic regions responsible for the remaining disease phenotypes remain largely uncharacterized. Here we explored two ICF1 patient-induced pluripotent stem cells (iPSCs) and their CRISPR/Cas9 corrected clones to determine whether gene correction can overcome DNA methylation defects and related/associated changes in the epigenome of non-repetitive regions.ResultsHypomethylated regions throughout the genome are highly comparable between ICF1 iPSCs carrying different DNMT3B variants, and significantly overlap with those in ICF1-peripheral blood and lymphoblastoid cell lines. These regions include large CpG island domains, as well as promoters and enhancers of several lineage-specific genes, in particular immune-related, suggesting that they are pre- marked during early development. The gene corrected ICF1 iPSCs reveal that the majority of phenotype- related hypomethylated regions re-acquire normal DNA methylation levels following editing. However, at the most severely hypomethylated regions in ICF1 iPSCs, which also display the highest increased H3K4me3 levels and enrichment of CTCF-binding motifs, the epigenetic memory persisted, and hypomethylation was uncorrected.ConclusionsRestoring the catalytic activity of DNMT3B rescues the majority of the aberrant ICF1 epigenome. However, a small fraction of the genome is resilient to this reversal, highlighting the challenge of reverting disease states that are due to genome-wide epigenetic perturbations. Uncovering the basis for the persistent epigenetic memory will promote the development of strategies to overcome this obstacle.

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DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity

Cited by 43 publications

References 118 publications

Cell division drives DNA methylation loss in late-replicating domains in primary human cells

Cell division drives DNA methylation loss in late-replicating domains in primary human cells

Exploring the effects of genetic variation on gene regulation in cancer in the context of 3D genome structure

The rescue of epigenomic abnormalities in ICF1 patient iPSCs following DNMT3B correction is incomplete at a residual fraction of H3K4me3-enriched regions

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