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53BP1 Contributes to Igh Locus Chromatin Topology during Class Switch Recombination

Scott Feldman1, Robert Wuerffel1, Ikbel Achour1

  • 1Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344; and.

Journal of Immunology (Baltimore, Md. : 1950)
|February 5, 2017
PubMed

Insights

53BP1 protein is crucial for organizing the three-dimensional structure of the immunoglobulin heavy chain (Igh) locus in mouse B cells, ensuring deletional class switch recombination (CSR) occurs correctly.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Immunoglobulin class switch recombination (CSR) is a vital process in B lymphocytes for antibody diversification.
  • CSR involves DNA double-strand breaks in switch (S) regions, followed by repair mechanisms.
  • The protein 53BP1 is known to be essential for deletional CSR but its precise role is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which 53BP1 facilitates deletional CSR and inhibits inversional switching.
  • To investigate the architectural role of 53BP1 in immunoglobulin heavy chain (Igh) locus chromatin looping.
  • To determine the specificity and regulation of 53BP1 chromatin occupancy.

Main Methods:

  • Studied chromatin looping interactions within the Igh locus in mouse B cells using 53BP1-deficient models.
  • Assessed the impact of 53BP1 deficiency on enhancer-promoter interactions (Eμ-3'Eα and germline transcript promoter-3'Eα).
  • Analyzed 53BP1 chromatin occupancy, its correlation with histone modifications (H4K20), and its spreading in B cells.

Main Results:

  • 53BP1 is essential for maintaining long-range chromatin looping between the Eμ and 3'Eα enhancers in the Igh locus.
  • Loss of 53BP1 significantly diminishes these specific long-range interactions, while others remain unaffected.
  • 53BP1 occupancy is B cell-specific, linked to H4K20 methylation, and exhibits chromatin spreading.

Conclusions:

  • 53BP1 plays a novel architectural role in the three-dimensional organization of the Igh locus.
  • This structural role of 53BP1 is critical for enforcing deletional CSR and preventing inversional switching.
  • The findings provide a mechanistic explanation for 53BP1's function in regulating CSR outcomes.

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