Replication timing and epigenome remodelling are associated with the nature of chromosomal rearrangements in cancer

Qian Du, Saul A. Bert, Nicola J. Armstrong, C. Elizabeth Caldon, Jenny Z. Song, Shalima S. Nair, Cathryn M. Gould, Phuc-Loi Luu, Timothy Peters, Amanda Khoury, Wenjia Qu, Elena Zotenko, Clare Stirzaker and Susan J. Clark ()
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Qian Du: Garvan Institute of Medical Research
Saul A. Bert: Garvan Institute of Medical Research
Nicola J. Armstrong: Murdoch University
C. Elizabeth Caldon: UNSW Sydney
Jenny Z. Song: Garvan Institute of Medical Research
Shalima S. Nair: Garvan Institute of Medical Research
Cathryn M. Gould: Garvan Institute of Medical Research
Phuc-Loi Luu: Garvan Institute of Medical Research
Timothy Peters: Garvan Institute of Medical Research
Amanda Khoury: Garvan Institute of Medical Research
Wenjia Qu: Garvan Institute of Medical Research
Elena Zotenko: Garvan Institute of Medical Research
Clare Stirzaker: Garvan Institute of Medical Research
Susan J. Clark: Garvan Institute of Medical Research

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08302-1

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