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A SNP uncoupling Mina expression from the TGFβ signaling pathway

Immunity, Inflammation and Disease. 2018;6(1):58-71 DOI 10.1002/iid3.191

 

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Journal Title: Immunity, Inflammation and Disease

ISSN: 2050-4527 (Online)

Publisher: Wiley

LCC Subject Category: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Shang L. Lian (St. Jude Children's Research Hospital262 Danny Thomas Place St.MemphisTN 38105USA)

Belgacem Mihi (St. Jude Children's Research Hospital262 Danny Thomas Place St.MemphisTN 38105USA)

Madoka Koyanagi (St. Jude Children's Research Hospital262 Danny Thomas Place St.MemphisTN 38105USA)

Toshinori Nakayama (Department of ImmunologyGraduate School of MedicineChiba University1‐8‐1 InohanaChuo‐kuChiba 260‐8670Japan)

Mark Bix (Institute for Global Prominent ResearchChiba University1‐8‐1 InohanaChuo‐kuChiba 260‐8670Japan)

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Time From Submission to Publication: 8 weeks

 

Abstract | Full Text

Abstract Introduction Mina is a JmjC family 2‐oxoglutarate oxygenase with pleiotropic roles in cell proliferation, cancer, T cell differentiation, pulmonary inflammation, and intestinal parasite expulsion. Although Mina expression varies according to cell‐type, developmental stage and activation state, its transcriptional regulation is poorly understood. Across inbred mouse strains, Mina protein level exhibits a bimodal distribution, correlating with inheritance of a biallelic haplotype block comprising 21 promoter/intron 1‐region SNPs. We previously showed that heritable differences in Mina protein level are transcriptionally regulated. Methods Accordingly, we decided to test the hypothesis that at least one of the promoter/intron 1‐region SNPs perturbs a Mina cis‐regulatory element (CRE). Here, we have comprehensively scanned for CREs across a Mina locus‐spanning 26‐kilobase genomic interval. Results We discovered 8 potential CREs and functionally validated 4 of these, the strongest of which (E2), residing in intron 1, contained a SNP whose BALB/c—but not C57Bl/6 allele—abolished both Smad3 binding and transforming growth factor beta (TGFβ) responsiveness. Conclusions Our results demonstrate the TGFβ signaling pathway plays a critical role in regulating Mina expression and SNP rs4191790 controls heritable variation in Mina expression level, raising important questions regarding the evolution of an allele that uncouples Mina expression from the TGFβ signaling pathway.