Abstract
DNA replication timing is known to facilitate the establishment of the epigenome, however, the intimate connection between replication timing and changes to the genome and epigenome in cancer remain largely uncharacterised. Here, we perform Repli-Seq and integrated epigenome analyses and demonstrate that genomic regions that undergo long-range epigenetic deregulation in prostate cancer also show concordant differences in replication timing. A subset of altered replication timing domains are conserved across cancers from different tissue origins. Notably, late-replicating regions in cancer cells display a loss of DNA methylation, and a switch in heterochromatin features from H3K9me3-marked constitutive to H3K27me3-marked facultative heterochromatin. Finally, analysis of 214 prostate and 35 breast cancer genomes reveal that late-replicating regions are prone to cis and early-replication to trans chromosomal rearrangements. Together, our data suggests that the nature of chromosomal rearrangement in cancer is related to the spatial and temporal positioning and altered epigenetic states of early-replicating compared to late-replicating loci.
Highlights
DNA replication timing is known to facilitate the establishment of the epigenome, the intimate connection between replication timing and changes to the genome and epigenome in cancer remain largely uncharacterised
Only 5.7% of the genome showed a difference in replication timing; 3.2% of the genome replicated later in LNCaP compared to prostate cells (PrEC) (ΔWA < −25), and 2.5% replicated earlier in LNCaP compared to PrEC (ΔWA > 25) (Supplementary Figure 1g)
To identify domains of consecutive loci where the time of replication is altered, we merged all loci within 50 kb that had a |ΔWA| > 25, and found 314 domains replicated later and 244 domains replicated earlier in LNCaP compared to PrEC
Summary
DNA replication timing is known to facilitate the establishment of the epigenome, the intimate connection between replication timing and changes to the genome and epigenome in cancer remain largely uncharacterised. We and others have previously shown that epigenetic deregulation in cancer can span large domains of long-range epigenetic silencing (LRES) and activation (LREA) with coordinated gene expression, histone modification, DNA methylation changes and disruption of topologically associated domains (TADs) over several kilobases to megabases[16,17,18]. Given the long-range domain level of epigenetic change observed in cancer, we were motivated to ask what is the relationship between replication timing and associated alterations to the epigenome and genome in cancer. We use high-resolution epigenome and genome-wide characterisation of normal and cancer cells to investigate how the replication timing landscape is associated with the cancer-specific epigenome changes and chromosomal rearrangements observed in prostate and breast cancers. We find that the differences in epigenetic deregulation between early and late replication underpin long-range epigenetic deregulation and potentially shape the nature of cancer mutational landscape
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