CTCF mediates insulator function at the CFTR locus

Neil P. Blackledge, Emma J. Carter, Joanne R. Evans, Victoria Lawson, Rebecca K. Rowntree, Ann Harris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Regulatory elements that lie outside the basal promoter of a gene may be revealed by local changes in chromatin structure and histone modifications. The promoter of the CFTR (cystic fibrosis transmembrane conductance regulator) gene is not responsible for its complex pattern of expression. To identify important regulatory elements for CFTR we have previously mapped DHS (DNase I-hypersensitive sites) across 400 kb spanning the locus. Of particular interest were two DHS that flank the CFTR gene, upstream at -20.9 kb with respect to the translational start site, and downstream at +15.6kb. In the present study we show that these two DHS possess enhancer-blocking activity and bind proteins that are characteristic of known insulator elements. The DHS core at -20.9 kb binds CTCF (CCCTC-binding factor) both in vitro and in vivo; however, the +15.6 kb core appears to bind other factors. Histone-modification analysis across the CFTR locus highlights structural differences between the -20.9 kb and +15.6 kb DHS, further suggesting that these two insulator elements may operate by distinct mechanisms. We propose that these two DHS mark the boundaries of the CFTR gene functional unit and establish a chromatin domain within which the complex profile of CFTR expression is maintained.

Original languageEnglish (US)
Pages (from-to)267-275
Number of pages9
JournalBiochemical Journal
Volume408
Issue number2
DOIs
StatePublished - Dec 1 2007

Keywords

  • CCCTC-binding factor (CTCF)
  • Chromatin structure
  • Cystic fibrosis transmembrane conductance regulator (CFTR)
  • DNase I-hypersensitive site
  • Histone modification
  • Insulator

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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