Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains

A Marieke Oudelaar, James O J Davies, Lars L P Hanssen, Jelena M Telenius, Ron Schwessinger, Yu Liu, Jill M Brown, Damien J Downes, Andrea M Chiariello, Simona Bianco, Mario Nicodemi, Veronica J Buckle, Job Dekker, Douglas R Higgs, Jim R Hughes

Research output: Contribution to journalArticlepeer-review

131 Scopus citations

Abstract

The promoters of mammalian genes are commonly regulated by multiple distal enhancers, which physically interact within discrete chromatin domains. How such domains form and how the regulatory elements within them interact in single cells is not understood. To address this we developed Tri-C, a new chromosome conformation capture (3C) approach, to characterize concurrent chromatin interactions at individual alleles. Analysis by Tri-C identifies heterogeneous patterns of single-allele interactions between CTCF boundary elements, indicating that the formation of chromatin domains likely results from a dynamic process. Within these domains, we observe specific higher-order structures that involve simultaneous interactions between multiple enhancers and promoters. Such regulatory hubs provide a structural basis for understanding how multiple cis-regulatory elements act together to establish robust regulation of gene expression.

Original languageEnglish
Pages (from-to)1744-1751
Number of pages8
JournalNature Genetics
Volume50
Issue number12
DOIs
StatePublished - Nov 2018

Keywords

  • Alleles
  • Animals
  • Base Sequence
  • Binding Sites/genetics
  • Cells, Cultured
  • Chromatin/chemistry
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation, Developmental
  • Genetic Loci
  • Globins/genetics
  • Linkage Disequilibrium
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Transcription Factors/metabolism

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