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


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.

Type Journal
ISBN 2211-1247 (Electronic)
Authors Du, Q.; Smith, G. C.; Luu, P. L.; Ferguson, J. M.; Armstrong, N. J.; Caldon, C. E.; Campbell, E. M.; Nair, S. S.; Zotenko, E.; Gould, C. M.; Buckley, M.; Chia, K. M.; Portman, N.; Lim, E.; Kaczorowski, D.; Chan, C. L.; Barton, K.; Deveson, I. W.; Smith, M. A.; Powell, J. E.; Skvortsova, K.; Stirzaker, C.; Achinger-Kawecka, J.; Clark, S. J.
Responsible Garvan Author Prof Susan Clark
Publisher Name Cell Reports
Published Date 2021-09-30
Published Volume 36
Published Issue 12
Published Pages 109722
Status Published in-print
DOI 10.1016/j.celrep.2021.109722
URL link to publisher's version