Loss of Ezh2 function remodels the DNA replication initiation landscape

Paulina Prorok, Faezeh Forouzanfar, Nerea Murugarren, Isabelle Peiffer, Romain Charton, Ildem Akerman, Marcel Méchali

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Abstract

In metazoan cells, DNA replication initiates from thousands of genomic loci scattered throughout the genome called DNA replication origins. Origins are strongly associated with euchromatin, particularly open genomic regions such as promoters and enhancers. However, over a third of transcriptionally silent genes are associated with DNA replication initiation. Most of these genes are bound and repressed by the Polycomb repressive complex-2 (PRC2) through the repressive H3K27me3 mark. This is the strongest overlap observed for a chromatin regulator with replication origin activity. Here, we asked whether Polycomb-mediated gene repression is functionally involved in recruiting DNA replication origins to transcriptionally silent genes. We show that the absence of EZH2, the catalytic subunit of PRC2, results in increased DNA replication initiation, specifically in the vicinity of EZH2 binding sites. The increase in DNA replication initiation does not correlate with transcriptional de-repression or the acquisition of activating histone marks but does correlate with loss of H3K27me3 from bivalent promoters.

Original languageEnglish
Article number112280
Number of pages16
JournalCell Reports
Volume42
Issue number4
Early online date29 Mar 2023
DOIs
Publication statusPublished - 25 Apr 2023

Bibliographical note

Copyright © 2023. Published by Elsevier Inc.

Keywords

  • DNA replication origins
  • polycomb
  • SNS-seq
  • PRC2
  • EZH2 knockout
  • bivalent promoters
  • H3K27me3
  • chromatin
  • DNA replication initiation

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