Regulation of Janus Kinase 2 by an Inflammatory Bowel Disease Causal Non-coding Single Nucleotide Polymorphism

Background and Aims Among the >240 genetic loci described to date which confer susceptibility to inflammatory bowel disease, a small subset have been fine-mapped to an individual, non-coding single nucleotide polymorphism [SNP]. To illustrate a model mechanism by which a presumed-causal non-coding SNP can function, we analysed rs1887428, located in the promoter region of the Janus kinase 2 [JAK2] gene. Methods We utilized comparative affinity purification-mass spectrometry, DNA–protein binding assays, CRISPR/Cas9 genome editing, transcriptome sequencing and methylome quantitative trait locus methods to characterize the role of this SNP. Results We determined that the risk allele of rs1887428 is bound by the transcription factor [TF] RBPJ, while the protective allele is bound by the homeobox TF CUX1. While rs188748 only has a very modest influence on JAK2 expression, this effect was amplified downstream through the expression of pathway member STAT5B and epigenetic modification of the JAK2 locus. Conclusion Despite the absence of a consensus TF-binding motif or expression quantitative trait locus, we have used improved methods to characterize a putatively causal SNP to yield insight into inflammatory bowel disease mechanisms. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast