Computational STAT4 rSNP Analysis, Transcriptional Factor Binding Sites And Disease

Norman E Buroker,Liang Liu

doi:10.14302/issn.2374-9431.jbd-15-890

Abstract

Purpose : The DIO2 gene transcribes the deiodinase type 2 enzyme that changes the thyroid prohormone, thyroxine (T4), to the biologically active triiodothyronine (T3) hormone. T3 plays a vital part in the regulation of energy balance and glucose metabolism. DIO2 single - nucleotide polymorphisms (SNPs) were computationally examined with respect to changes in punitive transc riptional factor binding sites (TFBS) and these changes were discussed in relation to human disease. Methods : The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in loc ating all the TFBS in the DIO2 gene from 2.4 kb upstream of the transcriptional start site to 508 bp past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results : Regulatory SNPs (rSNPs) i n the promoter region novel SNP ( - 2035bp), 5’UTR (rs12885300), intron one (rs225010, 225011 and rs225012), exon two [rs225014 (Thr92Ala)] and 3’ UTR (rs6574549, rs225015 and rs225017) of the DIO2 gene are in linkage disequilibrium. These rSNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. Conclusion : The alleles of each rSNP were found to generate unique TFBS resulting in potential Short Research Article

Highlights

The Janus Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) pathways play a critical role in immune, neuronal, hematopoietic and hepatic systems [1]
Due to the importance of this gene in signal transduction and activation of transcription, Signal Transducer and Activator of Transcription 4 (STAT4) simple nucleotide polymorphisms (SNPs) associated with disease were computationally evaluated with regard to transcriptional factor binding sites (TFBS)
The common rs7574865 SNP STAT4-G allele creates three unique TFBS for the FOXL1, MAX and ZNF354C transcriptional factors (TFs), which are involved with the regulation of metabolism, cell proliferation and gene expression during ontogenesis, transcription regulation and repression, respectively (Table 2, Appendix)

Summary

Introduction

The Janus Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) pathways play a critical role in immune, neuronal, hematopoietic and hepatic systems [1]. The STAT portion of the signaling cascade has seven mammalian family members which are STAT1, 2, 3, 4, 5a, 5b and 6 [3, 4]. These STATs bind thousands of transcriptional factor binding sites (TFBS) in the genome and regulate the transcription of many protein-coding genes, miRNAs and long noncoding RNAs [4]. STAT4 transduces IL-12, IL-23 and type 1 interferon-mediated signals into helper T (Th) cells (Th1 and Th17) differentiation, monocyte activation, and interferon-gamma production [12, 13]. The STAT4-dependent cytokine regulation is found in the pathogenesis of autoimmune disease [14, 15] such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [16, 17]

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Conclusion