Cell Reports (Sep 2021)
DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity
- Qian Du,
- Grady C. Smith,
- Phuc Loi Luu,
- James M. Ferguson,
- Nicola J. Armstrong,
- C. Elizabeth Caldon,
- Elyssa M. Campbell,
- Shalima S. Nair,
- Elena Zotenko,
- Cathryn M. Gould,
- Michael Buckley,
- Kee-Ming Chia,
- Neil Portman,
- Elgene Lim,
- Dominik Kaczorowski,
- Chia-Ling Chan,
- Kirston Barton,
- Ira W. Deveson,
- Martin A. Smith,
- Joseph E. Powell,
- Ksenia Skvortsova,
- Clare Stirzaker,
- Joanna Achinger-Kawecka,
- Susan J. Clark
Affiliations
- Qian Du
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Grady C. Smith
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Phuc Loi Luu
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- James M. Ferguson
- The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Nicola J. Armstrong
- Mathematics and Statistics, Murdoch University, Murdoch, WA 6150, Australia
- C. Elizabeth Caldon
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Elyssa M. Campbell
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Shalima S. Nair
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Elena Zotenko
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Cathryn M. Gould
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Michael Buckley
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Kee-Ming Chia
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Neil Portman
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Elgene Lim
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Dominik Kaczorowski
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Chia-Ling Chan
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Kirston Barton
- The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Ira W. Deveson
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia; The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Martin A. Smith
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia; The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Joseph E. Powell
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; UNSW Cellular Genomics Futures Institute, School of Medical Sciences, UNSW Sydney, NSW 2010, Australia
- Ksenia Skvortsova
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Clare Stirzaker
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Joanna Achinger-Kawecka
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Susan J. Clark
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia; Corresponding author
- Journal volume & issue
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Vol. 36,
no. 12
p. 109722
Abstract
Summary: DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation.
