Sequential Enhancer Sequestration Dysregulates Recombination Center Formation at the IgH Locus

Xiang Qiu, Gita Kumari, Tatiana Gerasimova, Hansen Du, Lawal Labaran, Amit Singh, Supriyo De, William H. Wood, Kevin G. Becker, Weiqiang Zhou, Hongkai Ji, Ranjan Sen

Research output: Contribution to journalArticlepeer-review

Abstract

Immunoglobulin heavy-chain (IgH) genes are assembled by DNA rearrangements that juxtapose a variable (VH), a diversity (DH), and a joining (JH) gene segment. Here, we report that in the absence of intergenic control region 1 (IGCR1), the intronic enhancer (Eμ) associates with the next available CTCF binding site located close to VH81X via putative heterotypic interactions involving YY1 and CTCF. The alternate Eμ/VH81X loop leads to formation of a distorted recombination center and altered DH rearrangements and disrupts chromosome conformation that favors distal VH recombination. Cumulatively, these features drive highly skewed, Eμ-dependent recombination of VH81X. Sequential deletion of CTCF binding regions on IGCR1-deleted alleles suggests that they influence recombination of single proximal VH gene segments. Our observations demonstrate that Eμ interacts differently with IGCR1- or VH-associated CTCF binding sites and thereby identify distinct roles for insulator-like elements in directing enhancer activity. Qiu et al. highlight mechanisms by which enhancer sequestration by different CTCF sites shapes chromatin structure to regulate DNA rearrangement at the IgH locus. Their observations identify distinct roles for insulator-like elements in modulating enhancer function.

Original languageEnglish (US)
Pages (from-to)21-33.e6
JournalMolecular cell
Volume70
Issue number1
DOIs
StatePublished - Apr 5 2018

Keywords

  • CTCF binding element
  • IGCR1
  • IgH
  • enhancer
  • recombination center

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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