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

J Crohns Colitis. 2020 Jun 19;14(5):646-653. doi: 10.1093/ecco-jcc/jjz213.


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.

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Keywords: Gene regulation; comparative proteomics; single nucleotide polymorphism.