Genome-wide association studies(GWASs)have identified over 100 loci associated with rheumatoid arthritis(RA);how-ever,the functionally affected genes and the underlying molecular mechanisms contributing to these associations are often unknown.In this study,we conducted an integrative genomic analysis incorporating multiple“omics”data and identified a functional regulatory DNA variant,rs56199421,and a plausible mechanism by which it regulates the expression of a puta-tive RA risk gene,ORMDL Sphingolipid Biosynthesis Regulator 3(ORMDL3).The T allele of rs56199421,located in the enhancer region of ORMDL3,exhibited stronger direct binding ability than the other C allele of rs56199421 did in vitro with the transcription factor JunD and demonstrated higher transcriptional activity.Moreover,the T allele of rs56199421 is associated with elevated RA risk,and ORMDL3 expression is increased in RA patients.Thus,these findings suggest that the T allele of rs56199421 enhances JunD transcription factor binding,increases enhancer activity,and elevates the expression of the RA risk gene ORMDL3.
Activating protein-1(AP-1)composed of Jun and Fos family proteins,which are frequently activated by pathogens to induce cellular inflammation and immune responses.In this study,by using RNA sequencing(RNA-seq)technology,we found that FosB,Fosl2,and JunD expression was co-induced 12 and 20 h in grass carp(Ctenopharyngodon idella)kidney cell line(CIK cells)after grass carp reovirus(GCRV)infection.Full-length cDNA of the three genes were cloned and phylogenetic analysis indicated that the corresponding proteins shared high homology with those in higher vertebrates.The tissue distribution analysis of the three genes showed they were ubiquitously expressed in various tissues of healthy grass carp.In infection assay,FosB,Fosl2,and JunD were up-regulated and co-expressed 8 h after GCRV infection in CIK cells.Protein interaction and co-expression network analysis revealed that FosB,Fosl2,and JunD showed similar functions and were co-expressed in mammals and fish.Taken together,these results indicated that the co-expression of the AP-1 family proteins in grass carp uniformly responds to GCRV infection.These findings provided insights into the further study of AP-1 transcription factors function during grass carp reovirus infection.
Fei YuWanjuan LiLonglong WangShunzheng QueLiqun Lu
