Characterising a Novel Therapeutic Target for Psoriasis, TYK2, Using Functional Genomics

Area of Science:

• Genetics and Immunology
• Molecular Biology
• Dermatology

Background:

• Psoriasis (Ps) is a chronic immune-mediated skin disease affecting 1-3% of the global population.
• Tyrosine kinase 2 (TYK2) is a validated therapeutic target for Ps.
• Genetic associations suggest non-coding variants upstream of TYK2 influence its expression and Ps risk.

Purpose of the Study:

• To investigate if Single-Nucleotide Polymorphisms (SNPs) near ILF3 act as distal regulators of TYK2 expression and Psoriasis (Ps) risk.
• To elucidate the role of TYK2 pathway dysregulation in Ps pathogenesis.
• To identify downstream genes regulated by these risk SNPs.

Main Methods:

• Developed CRISPR activation and inhibition systems in Jurkat T cells to manipulate specific Ps risk variants (rs892086, rs7248205).
• Employed functional genomics and molecular biology techniques to assess gene regulation.
• Utilized RNA-sequencing (RNA-seq) to analyze differential gene expression in the TYK2 pathway.

Main Results:

• Demonstrated that distal risk SNPs, located upstream of TYK2, can indeed regulate TYK2 gene expression.
• Identified differentially expressed genes including VEGFA, C1R, ADORA1, GLUD2, NDUFB8, and FCGR2C, implicated in Ps and other inflammatory conditions.
• Confirmed the relevance of these genes in inflammatory conditions through database comparisons.

Conclusions:

• The study confirms that non-coding genetic variants can distally regulate TYK2 expression, contributing to Psoriasis (Ps) risk.
• The identified downstream genes offer potential biomarkers and therapeutic targets within the TYK2 pathway.
• This research enhances the understanding of Psoriasis (Ps) disease biology through advanced genetic and molecular approaches.