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A SNP uncoupling Mina expression from the TGFβ signaling pathway.

Shang L Lian1, Belgacem Mihi1, Madoka Koyanagi1

  • 1St. Jude Children's Research Hospital, 262 Danny Thomas Place St., Memphis, TN 38105, USA.

Immunity, Inflammation and Disease
|October 3, 2017
PubMed
Summary

Genetic variations in mouse strains affect Mina protein levels due to differences in cis-regulatory elements. A specific single nucleotide polymorphism (SNP) in the Mina gene disrupts transforming growth factor beta (TGFβ) signaling, impacting gene expression.

Keywords:
Cis regulatory elementMinaRiox2TGFβenhancergene regulation

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Area of Science:

  • Genetics
  • Molecular Biology
  • Immunology

Background:

  • Mina, a JmjC family 2-oxoglutarate oxygenase, has diverse roles in cell proliferation, cancer, T cell differentiation, inflammation, and parasite expulsion.
  • Transcriptional regulation of Mina is not well understood, despite its varied expression.
  • Heritable differences in Mina protein levels across mouse strains correlate with specific genetic variations in its promoter/intron 1 region.

Purpose of the Study:

  • To investigate the hypothesis that single nucleotide polymorphisms (SNPs) in the Mina promoter/intron 1 region affect cis-regulatory elements (CREs).
  • To identify and functionally validate CREs within the Mina locus that contribute to heritable differences in Mina expression.

Main Methods:

  • Comprehensive scanning for CREs across a 26-kilobase genomic interval of the Mina locus.
  • Functional validation of identified CREs.
  • Analysis of SNP effects on transcription factor binding (Smad3) and pathway responsiveness (TGFβ).

Main Results:

  • Eight potential CREs were identified within the Mina locus.
  • Four CREs were functionally validated, with one strong CRE (E2) in intron 1 showing significant results.
  • A specific SNP within the E2 CRE altered Smad3 binding and abolished transforming growth factor beta (TGFβ) responsiveness in a strain-dependent manner (BALB/c vs. C57Bl/6).

Conclusions:

  • The transforming growth factor beta (TGFβ) signaling pathway is crucial for regulating Mina expression.
  • SNP rs4191790 is identified as a key determinant of heritable variation in Mina expression levels.
  • The findings raise questions about the evolutionary implications of an allele that decouples Mina expression from TGFβ signaling.