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U2AF2 binds IL7R exon 6 ectopically and represses its inclusion.

Geraldine Schott1, Gaddiel Galarza-Muñoz1,2, Noe Trevino1

  • 1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.

RNA (New York, N.Y.)
|February 11, 2021
PubMed
Summary

Interleukin 7 receptor alpha-chain (IL7R) exon 6 splicing, linked to multiple sclerosis (MS) risk, is regulated by splicing factor competition and U2AF2 binding. The MS-associated allele enhances exon skipping, increasing soluble IL7R levels.

Keywords:
IL7RU2AF2alternate splicingmultiple sclerosis

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Area of Science:

  • Immunology
  • Molecular Biology
  • Neuroscience

Background:

  • Interleukin 7 receptor alpha-chain (IL7R) is vital for T cell development and linked to autoimmune disorders like multiple sclerosis (MS).
  • Alternative splicing of IL7R exon 6 generates membrane-bound or soluble isoforms, with exon skipping linked to increased MS risk.
  • A specific SNP (rs6897932) in exon 6 is associated with MS, where the risk allele (C) promotes exon skipping and elevated soluble IL7R.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating IL7R exon 6 alternative splicing.
  • To understand how the MS-associated risk allele influences IL7R splicing and soluble receptor levels.

Main Methods:

  • Investigated splicing factor competition (PTBP1 vs. U2AF2) at intron 5 polypyrimidine tract.
  • Analyzed U2AF2-mediated splicing factor assembly within exon 6.
  • Examined evolutionary conservation of exonic sequences and U2AF2 binding.
  • Assessed the impact of the rs6897932 risk allele on splicing factor interactions.

Main Results:

  • Two novel mechanisms controlling IL7R exon 6 splicing were identified: PTBP1/U2AF2 competition and U2AF2-mediated exon assembly.
  • A branchpoint sequence (BPS) within exon 6, stronger with the risk allele (C), facilitates U2AF2 binding.
  • Evolutionary conservation of the exonic polypyrimidine tract (PPT) correlates with alternative splicing extent.
  • U2AF2 binding to the exonic PPT recruits U2 snRNP, explaining enhanced exon 6 skipping with the risk allele.

Conclusions:

  • The study reveals dual regulatory mechanisms for IL7R exon 6 splicing, involving both intronic and exonic sequences.
  • The MS-associated risk allele at rs6897932 enhances IL7R exon 6 skipping via a U2AF2-dependent mechanism.
  • These findings provide critical mechanistic insights into how IL7R genetic variations contribute to multiple sclerosis pathogenesis.