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CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells

Academic Article
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Overview

authors

  • Degner, S. C.
  • Verma-Gaur, J.
  • Wong, T. P.
  • Bossen, C.
  • Iverson, G. M.
  • Torkamani, Ali
  • Vettermann, C.
  • Lin, Y. C.
  • Ju, Z. L.
  • Schulz, D.
  • Murre, C. S.
  • Birshtein, B. K.
  • Schork, Nicholas
  • Schlissel, M. S.
  • Riblet, R.
  • Murre, C.
  • Feeney, Ann

publication date

  • June 2011

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Compaction and looping of the ~2.5-Mb Igh locus during V(D)J rearrangement is essential to allow all V(H) genes to be brought in proximity with D(H)-J(H) segments to create a diverse antibody repertoire, but the proteins directly responsible for this are unknown. Because CCCTC-binding factor (CTCF) has been demonstrated to be involved in long-range chromosomal interactions, we hypothesized that CTCF may promote the contraction of the Igh locus. ChIP sequencing was performed on pro-B cells, revealing colocalization of CTCF and Rad21 binding at ~60 sites throughout the V(H) region and 2 other sites within the Igh locus. These numerous CTCF/cohesin sites potentially form the bases of the multiloop rosette structures at the Igh locus that compact during Ig heavy chain rearrangement. To test whether CTCF was involved in locus compaction, we used 3D-FISH to measure compaction in pro-B cells transduced with CTCF shRNA retroviruses. Reduction of CTCF binding resulted in a decrease in Igh locus compaction. Long-range interactions within the Igh locus were measured with the chromosomal conformation capture assay, revealing direct interactions between CTCF sites 5' of DFL16 and the 3' regulatory region, and also the intronic enhancer (Eμ), creating a D(H)-J(H)-Eμ-C(H) domain. Knockdown of CTCF also resulted in the increase of antisense transcription throughout the D(H) region and parts of the V(H) locus, suggesting a widespread regulatory role for CTCF. Together, our findings demonstrate that CTCF plays an important role in the 3D structure of the Igh locus and in the regulation of antisense germline transcription and that it contributes to the compaction of the Igh locus.

subject areas

  • Animals
  • Binding Sites
  • Blotting, Western
  • Cell Cycle Proteins
  • Cell Line
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Chromosomal Proteins, Non-Histone
  • DNA, Antisense
  • Enhancer Elements, Genetic
  • Immunoglobulin Heavy Chains
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins
  • Phosphoproteins
  • Precursor Cells, B-Lymphoid
  • Protein Binding
  • RNA Interference
  • RNA, Antisense
  • Repressor Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic
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Research

keywords

  • ChIP-seq
  • V(D)J recombination
  • boundary element
  • insulator
  • lymphocytes
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Identity

PubMed Central ID

  • PMC3111298

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1019391108

PubMed ID

  • 21606361
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Additional Document Info

start page

  • 9566

end page

  • 9571

volume

  • 108

issue

  • 23

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