A predictable conserved DNA base composition signature defines human core DNA replication origins

Ildem Akerman, Bahar Kasaai, Alina Bazarova, Pau Biak Sang, Isabelle Peiffer, Marie Artufel, Romain Derelle, Gabrielle Smith, Marta Rodriguez-Martinez, Manuela Romano, Sandrina Kinet, Peter Tino, Charles Theillet, Naomi Taylor, Benoit Ballester, Marcel Méchali

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
232 Downloads (Pure)

Abstract

DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.

Original languageEnglish
Article number4826
Number of pages15
JournalNature Communications
Volume11
Issue number1
Early online date21 Sept 2020
DOIs
Publication statusPublished - Dec 2020

Bibliographical note

Funding Information:
We warmly thank Harold Riethman, Benoit Miotto, Chunlong Chen, Oliver Hyrien and David Gilbert for providing details on their data. I.A. is supported by Diabetes UK RD Lawrence fellowship. This research received funding from the Association Française contre les Myopathies (AFM), the ARC foundation, the ANR14-CE10-0019, and by the MSD AVENIR Fund GENE-IGH. This work also benefited from support by the Labex EpiGenMed, an Investissements d’Avenir programme (reference ANR-10-LABX-12-0), and from a Pre-maturation support from the Region Occitanie.

Publisher Copyright:
© 2020, The Author(s).

Keywords

  • DNA replication origins
  • DNA replication initiation
  • TAD domains
  • cancer
  • p53
  • Heterochromatin/genetics
  • Humans
  • Cells, Cultured
  • DNA Replication/genetics
  • Carcinogenesis
  • Animals
  • Nucleotide Motifs
  • Base Composition
  • Replication Origin/genetics
  • Base Sequence
  • Genome, Human/genetics
  • DNA/biosynthesis
  • Transcription, Genetic
  • Cell Differentiation
  • Mice

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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