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

Cell Reports

Martin A. Smith¹  Kee-Ming Chia¹  Grady C. Smith¹  Elena Zotenko¹  Nicola J. Armstrong¹  Susan J. Clark²  Phuc Loi Luu³  Qian Du³  Elgene Lim³  James M. Ferguson³  Neil Portman³  Dominik Kaczorowski³  Michael Buckley³  Kirston Barton³  Ira W. Deveson³  Chia-Ling Chan³  Shalima S. Nair³  Cathryn M. Gould³  Joseph E. Powell⁴  Ksenia Skvortsova⁴  Elyssa M. Campbell⁵  Joanna Achinger-Kawecka⁶  C. Elizabeth Caldon⁷  Clare Stirzaker⁷ 

[1] 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;Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;Mathematics and Statistics, Murdoch University, Murdoch, WA 6150, Australia;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;

关键词: replication timing;    DNA methylation;    epigenome;    chromatin;    single-cell sequencing;    allele-specific replication;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown