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Exuberant long noncoding RNA expression may sculpt Igh locus topology.

Ellen B Drake1, Sarah Naiyer1, Xinyan Qu1

  • 1Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, United States.

Frontiers in Immunology
|December 10, 2025
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Summary

Long non-coding RNAs (lncRNAs) and cohesin-mediated loop extrusion are key to immunoglobulin heavy chain (Igh) gene recombination. This study reveals lncRNAs at the Igh locus influence V(D)J recombination and gene usage.

Keywords:
IgH locusV(D)J recombinationchromatin foldinglong non-coding RNAprogenitor B cells

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Diverse immunoglobulin heavy chain (Igh) repertoires are essential for adaptive immunity, relying on V(D)J recombination for B cell receptor expression and antibody secretion.
  • Igh locus contraction, facilitated by cohesin-mediated loop extrusion, brings distal V(D)J gene segments closer to the recombination center, but the mechanisms governing differential V(D)J gene usage remain unclear.

Purpose of the Study:

  • To investigate the role of long non-coding RNAs (lncRNAs) in regulating Igh locus topology and V(D)J recombination.
  • To elucidate the interplay between lncRNAs, enhancers, and chromatin looping in determining V(D)J gene segment accessibility and usage.

Main Methods:

  • Analysis of lncRNA expression at the immunoglobulin heavy chain (Igh) locus and other antigen receptor (AgR) loci.
  • Correlation analysis of lncRNA positions with Igh enhancers and chromatin loop anchors.
  • Integration of lncRNA function with cohesin-mediated loop extrusion models.

Main Results:

  • Exceptionally high expression of lncRNAs was observed at the Igh locus and other V(D)J recombination sites.
  • A strong correlation exists between the genomic locations of multi-exonic lncRNAs, Igh enhancers, and chromatin loop anchor points.
  • These findings suggest a coordinated role for lncRNAs and structural elements in shaping Igh locus architecture.

Conclusions:

  • lncRNAs are significantly expressed at the Igh locus and are spatially correlated with regulatory elements and chromatin loops.
  • An integrated model involving lncRNAs and loop extrusion is proposed to explain Igh locus topology and V(D)J recombination dynamics.
  • This study highlights a novel regulatory mechanism for V(D)J recombination, impacting B cell development and humoral immunity.