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
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.
