A SNP uncoupling Mina expression from the TGFβ signaling pathway
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 sta...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2018-03-01
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| Series: | Immunity, Inflammation and Disease |
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| Online Access: | https://doi.org/10.1002/iid3.191 |
| _version_ | 1818133674337501184 |
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| author | Shang L. Lian Belgacem Mihi Madoka Koyanagi Toshinori Nakayama Mark Bix |
| author_facet | Shang L. Lian Belgacem Mihi Madoka Koyanagi Toshinori Nakayama Mark Bix |
| author_sort | Shang L. Lian |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T08:56:28Z |
| format | Article |
| id | doaj.art-c72cb2afa1ad4524bed45fbb1a55e52e |
| institution | Directory Open Access Journal |
| issn | 2050-4527 |
| language | English |
| last_indexed | 2024-12-11T08:56:28Z |
| publishDate | 2018-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Immunity, Inflammation and Disease |
| spelling | doaj.art-c72cb2afa1ad4524bed45fbb1a55e52e2022-12-22T01:13:52ZengWileyImmunity, Inflammation and Disease2050-45272018-03-0161587110.1002/iid3.191A SNP uncoupling Mina expression from the TGFβ signaling pathwayShang L. Lian0Belgacem Mihi1Madoka Koyanagi2Toshinori Nakayama3Mark Bix4St. Jude Children's Research Hospital262 Danny Thomas Place St.MemphisTN 38105USASt. Jude Children's Research Hospital262 Danny Thomas Place St.MemphisTN 38105USASt. Jude Children's Research Hospital262 Danny Thomas Place St.MemphisTN 38105USADepartment of ImmunologyGraduate School of MedicineChiba University1‐8‐1 InohanaChuo‐kuChiba 260‐8670JapanInstitute for Global Prominent ResearchChiba University1‐8‐1 InohanaChuo‐kuChiba 260‐8670JapanAbstract 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.https://doi.org/10.1002/iid3.191Cis regulatory elementenhancerMinagene regulationRiox2TGFβ |
| spellingShingle | Shang L. Lian Belgacem Mihi Madoka Koyanagi Toshinori Nakayama Mark Bix A SNP uncoupling Mina expression from the TGFβ signaling pathway Immunity, Inflammation and Disease Cis regulatory element enhancer Mina gene regulation Riox2 TGFβ |
| title | A SNP uncoupling Mina expression from the TGFβ signaling pathway |
| title_full | A SNP uncoupling Mina expression from the TGFβ signaling pathway |
| title_fullStr | A SNP uncoupling Mina expression from the TGFβ signaling pathway |
| title_full_unstemmed | A SNP uncoupling Mina expression from the TGFβ signaling pathway |
| title_short | A SNP uncoupling Mina expression from the TGFβ signaling pathway |
| title_sort | snp uncoupling mina expression from the tgfβ signaling pathway |
| topic | Cis regulatory element enhancer Mina gene regulation Riox2 TGFβ |
| url | https://doi.org/10.1002/iid3.191 |
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