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Post-GWAS functional studies reveal an RA-associated CD40-induced NF-kB signal transduction and transcriptional regulation network targeted by class II HDAC inhibitors
- Source :
- Human Molecular Genetics
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
Abstract
- Currently, it remains difficult to identify which single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) are functional and how various functional SNPs (fSNPs) interact and contribute to disease susceptibility. GWAS have identified a CD40 locus that is associated with rheumatoid arthritis (RA). We previously used two techniques developed in our laboratory, single nucleotide polymorphism-next-generation sequencing (SNP-seq) and flanking restriction enhanced DNA pulldown-mass spectrometry (FREP-MS), to determine that the RA risk gene RBPJ regulates CD40 expression via a fSNP at the RA-associated CD40 locus. In the present work, by applying the same approach, we report the identification of six proteins that regulate RBPJ expression via binding to two fSNPs on the RA-associated RBPJ locus. Using these findings, together with the published data, we constructed an RA-associated signal transduction and transcriptional regulation network (STTRN) that functionally connects multiple RA-associated risk genes via transcriptional regulation networks (TRNs) linked by CD40-induced nuclear factor kappa B (NF-kB) signaling. Remarkably, this STTRN provides insight into the potential mechanism of action for the histone deacetylase inhibitor givinostat, an approved therapy for systemic juvenile idiopathic arthritis. Thus, the generation of disease-associated STTRNs based on post-GWAS functional studies is demonstrated as a novel and effective approach to apply GWAS for mechanistic studies and target identification.
- Subjects :
- AcademicSubjects/SCI01140
medicine.drug_class
Locus (genetics)
Single-nucleotide polymorphism
Genome-wide association study
Computational biology
Biology
Polymorphism, Single Nucleotide
Arthritis, Rheumatoid
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Genetics
Transcriptional regulation
medicine
Humans
Genetic Predisposition to Disease
Association Studies Article
Givinostat
Molecular Biology
Gene
Genetics (clinical)
030304 developmental biology
0303 health sciences
RBPJ
Histone deacetylase inhibitor
NF-kappa B
General Medicine
Histone Deacetylase Inhibitors
chemistry
030220 oncology & carcinogenesis
Genome-Wide Association Study
Signal Transduction
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....6a0709c42e2dee9e3492df2f671f4e35