ERCC1-XPF cooperates with CTCF and cohesin to facilitate the developmental silencing of imprinted genes

Georgia Chatzinikolaou, Zivkos Apostolou, Tamara Aid-Pavlidis, Anna Ioannidou, Ismene Karakasilioti, Giorgio L Papadopoulos, Michalis Aivaliotis, Maria Tsekrekou, John Strouboulis, Theodore Kosteas, George A Garinis

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Inborn defects in DNA repair are associated with complex developmental disorders whose causal mechanisms are poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the nucleotide excision repair (NER) structure-specific endonuclease ERCC1-XPF complex interacts with the insulator binding protein CTCF, the cohesin subunits SMC1A and SMC3 and with MBD2; the factors co-localize with ATRX at the promoters and control regions (ICRs) of imprinted genes during postnatal hepatic development. Loss of Ercc1 or exposure to MMC triggers the localization of CTCF to heterochromatin, the dissociation of the CTCF-cohesin complex and ATRX from promoters and ICRs, altered histone marks and the aberrant developmental expression of imprinted genes without altering DNA methylation. We propose that ERCC1-XPF cooperates with CTCF and cohesin to facilitate the developmental silencing of imprinted genes and that persistent DNA damage triggers chromatin changes that affect gene expression programs associated with NER disorders.

Original languageEnglish
Pages (from-to)421-432
Number of pages12
JournalNature Cell Biology
Volume19
Issue number5
Early online date3 Apr 2017
DOIs
Publication statusPublished - 1 May 2017

Keywords

  • Age Factors
  • Animals
  • Animals, Newborn
  • CCCTC-Binding Factor
  • Cell Cycle Proteins/genetics
  • Cells, Cultured
  • Chondroitin Sulfate Proteoglycans/genetics
  • Chromosomal Proteins, Non-Histone/genetics
  • Coculture Techniques
  • DNA Damage
  • DNA Helicases/genetics
  • DNA Repair
  • DNA-Binding Proteins/genetics
  • Endonucleases/genetics
  • Fibroblasts/enzymology
  • Gene Expression Regulation, Developmental
  • Gene Silencing
  • Genomic Imprinting
  • Genotype
  • Histones/metabolism
  • Liver/enzymology
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins/genetics
  • Phenotype
  • Promoter Regions, Genetic
  • Repressor Proteins/genetics
  • X-linked Nuclear Protein

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