CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2

Sreenivasulu Kurukuti, Vijay Kumar Tiwari, Gholamreza Tavoosidana, Elena Pugacheva, Adele Murrell, Zhihu Zhao, Victor Lobanenkov, Wolf Reik, Rolf Ohlsson

Research output: Chapter in Book/Report/Conference proceedingChapter

360 Citations (Scopus)

Abstract

It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over >160 kb, identifying sequences that interact physically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome.
Original languageEnglish
Title of host publicationProceedings of the National Academy of Sciences
Pages10684-10689
Number of pages6
DOIs
Publication statusPublished - 2006

Publication series

NameProceedings of the National Academy of Sciences
Volume103

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Keywords

  • Animals
  • DNA-Binding Proteins
  • DNA-Binding Proteins: metabolism
  • DNA-Binding Proteins: physiology
  • Enhancer Elements
  • Epigenesis
  • Female
  • Gene Silencing
  • Genetic
  • Genetic: physiology
  • Genomic Imprinting
  • Genomic Imprinting: physiology
  • Heterochromatin
  • Heterochromatin: chemistry
  • Heterochromatin: genetics
  • Heterochromatin: metabolism
  • Insulin-Like Growth Factor II
  • Insulin-Like Growth Factor II: genetics
  • Insulin-Like Growth Factor II: metabolism
  • Long Noncoding
  • Male
  • Mice
  • Protein Binding
  • Protein Binding: genetics
  • Protein Conformation
  • Proteins
  • Proteins: genetics
  • RNA
  • Repressor Proteins
  • Repressor Proteins: metabolism
  • Repressor Proteins: physiology
  • Untranslated
  • Untranslated: metabolism
  • Untranslated: physiology

Cite this

Kurukuti, S., Tiwari, V. K., Tavoosidana, G., Pugacheva, E., Murrell, A., Zhao, Z., ... Ohlsson, R. (2006). CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. In Proceedings of the National Academy of Sciences (pp. 10684-10689). (Proceedings of the National Academy of Sciences; Vol. 103). https://doi.org/10.1073/pnas.0600326103