Skip to main content

U2AF2 binds IL7R exon 6 ectopically and represses its inclusion.

Publication ,  Journal Article
Schott, G; Galarza-Muñoz, G; Trevino, N; Chen, X; Weirauch, M; Gregory, SG; Bradrick, SS; Garcia-Blanco, MA
Published in: RNA
February 10, 2021

Interleukin 7 receptor α-chain is crucial for the development and maintenance of T cells and is genetically associated with autoimmune disorders including multiple sclerosis (MS), a demyelinating disease of the CNS. Exon 6 of IL7R encodes for the transmembrane domain of the receptor and is regulated by alternative splicing: inclusion or skipping of IL7R exon 6 results in membrane-bound or soluble IL7R isoforms, respectively. We previously identified a SNP (rs6897932) in IL7R exon 6, strongly associated with MS risk and showed that the risk allele (C) increases skipping of the exon, resulting in elevated levels of sIL7R. This has important pathological consequences as elevated levels of sIL7R has been shown to exacerbate the disease in the experimental autoimmune encephalomyelitis mouse model of MS. Understanding the regulation of exon 6 splicing provides important mechanistic insights into the pathogenesis of MS. Here we report two mechanisms by which IL7R exon 6 is controlled. First, a competition between PTBP1 and U2AF2 at the polypyrimidine tract (PPT) of intron 5, and second, an unexpected U2AF2-mediated assembly of spicing factors in the exon. We noted the presence of a branchpoint sequence (BPS) (TACTAAT or TACTAAC) within exon 6, which is stronger with the C allele. We also noted that the BPS is followed by a PPT and conjectured that silencing could be mediated by the binding of U2AF2 to that tract. In support of this model, we show that evolutionary conservation of the exonic PPT correlates well with the degree of alternative splicing of exon 6 in two non-human primate species and that U2AF2 binding to this PPT recruits U2 snRNP components to the exon. These observations provide the first explanation for the stronger silencing of IL7R exon 6 with the disease associated C allele at rs6897932.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

RNA

DOI

EISSN

1469-9001

Publication Date

February 10, 2021

Volume

27

Issue

5

Start / End Page

571 / 583

Location

United States

Related Subject Headings

  • Developmental Biology
  • 3101 Biochemistry and cell biology
  • 0601 Biochemistry and Cell Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Schott, G., Galarza-Muñoz, G., Trevino, N., Chen, X., Weirauch, M., Gregory, S. G., … Garcia-Blanco, M. A. (2021). U2AF2 binds IL7R exon 6 ectopically and represses its inclusion. RNA, 27(5), 571–583. https://doi.org/10.1261/rna.078279.120
Schott, Geraldine, Gaddiel Galarza-Muñoz, Noe Trevino, Xiaoting Chen, Matthew Weirauch, Simon G. Gregory, Shelton S. Bradrick, and Mariano A. Garcia-Blanco. “U2AF2 binds IL7R exon 6 ectopically and represses its inclusion.RNA 27, no. 5 (February 10, 2021): 571–83. https://doi.org/10.1261/rna.078279.120.
Schott G, Galarza-Muñoz G, Trevino N, Chen X, Weirauch M, Gregory SG, et al. U2AF2 binds IL7R exon 6 ectopically and represses its inclusion. RNA. 2021 Feb 10;27(5):571–83.
Schott, Geraldine, et al. “U2AF2 binds IL7R exon 6 ectopically and represses its inclusion.RNA, vol. 27, no. 5, Feb. 2021, pp. 571–83. Pubmed, doi:10.1261/rna.078279.120.
Schott G, Galarza-Muñoz G, Trevino N, Chen X, Weirauch M, Gregory SG, Bradrick SS, Garcia-Blanco MA. U2AF2 binds IL7R exon 6 ectopically and represses its inclusion. RNA. 2021 Feb 10;27(5):571–583.

Published In

RNA

DOI

EISSN

1469-9001

Publication Date

February 10, 2021

Volume

27

Issue

5

Start / End Page

571 / 583

Location

United States

Related Subject Headings

  • Developmental Biology
  • 3101 Biochemistry and cell biology
  • 0601 Biochemistry and Cell Biology