A SNP uncoupling Mina expression from the TGFβ signaling pathway

Abstract

IntroductionMina 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.MethodsAccordingly, 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.ResultsWe 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.ConclusionsOur 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.

Mdig promotes oncogenic gene expression through antagonizing repressive histone methylation markers

“…Furthermore, this finding also unraveled a forward feedback route between mdig and TGFβ. A recent comprehensive genetic study in BALB/C and C57BL/6 mice suggested that a single nucleotide polymorphism in the intron 1 region of mdig gene favors Smad3 binding, TGFβ responsiveness and mdig transcription 41.…”

The emerging roles of ribosomal histidyl hydroxylases in cell biology, physiology and disease

“…The authors speculated that this may be mediated via an independent role for MINA in promoting T H 2 cytokine expression in antigen presenting cells. Others have proposed that the reduced airway disease in this model may be associated with a defective Th17 response [ 77 ]. If correct, this would suggest that the known role of MINA in Th17 differentiation (outlined above) may be dominant with respect to its role in T H 2 bias, at least in this particular disease.…”

Quantitative Proteomics Reveals Docosahexaenoic Acid-Mediated Neuroprotective Effects in Lipopolysaccharide-Stimulated Microglial Cells

“…Ribosomal oxygenase 2 (RIOX2/MINA) is a histone lysine demethylase important in TNFb signaling 63 and is associated with cell proliferation in a number of cancers. 64 , 65 It is increased in the LPS group, but not detected in DHA or the LPS + DHA group, again indicating a protective effect of DHA.…”

“…62 In the study by Yang et al, 62 LPSs were observed to alter secretion of EVs by the activation of ribosomal assembly and translation, which may play a role in the detrimental inflammatory responses in neurodegenerative diseases. Ribosomal oxygenase 2 (RIOX2/MINA) is a histone lysine demethylase important in TNFb signaling 63 and is associated with cell proliferation in a number of cancers. 64,65 It is increased in the LPS group, but not detected in DHA or the LPS + DHA group, again indicating a protective effect of DHA.…”