Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian clock

Autoři: Matthew L. Chang aff001;  Sanny Moussette aff001;  Enrique Gamero-Estevez aff002;  José Héctor Gálvez aff003;  Victoria Chiwara aff002;  Indra R. Gupta aff001;  Aimee K. Ryan aff001;  Anna K. Naumova aff001
Působiště autorů: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada aff001;  Department of Human Genetics, McGill University, Montreal, Quebec, Canada aff002;  Canadian Centre for Computational Genomics, Montreal, Quebec, Canada aff003;  Department of Paediatrics, McGill University, Montreal, Quebec, Canada aff004;  Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223212


Genome-wide association study (GWAS) loci for several immunity-mediated diseases (early onset asthma, inflammatory bowel disease (IBD), primary biliary cholangitis, and rheumatoid arthritis) map to chromosomal region 17q12-q21. The predominant view is that association between 17q12-q21 alleles and increased risk of developing asthma or IBD is due to regulatory variants. ORM sphingolipid biosynthesis regulator (ORMDL3) residing in this region is the most promising gene candidate for explaining association with disease. However, the relationship between 17q12-q21 alleles and disease is complex suggesting contributions from other factors, such as trans-acting genetic and environmental modifiers or circadian rhythms. Circadian rhythms regulate expression levels of thousands of genes and their dysregulation is implicated in the etiology of several common chronic inflammatory diseases. However, their role in the regulation of the 17q12-q21 genes has not been investigated. Moreover, the core clock gene nuclear receptor subfamily 1, group D, member 1 (NR1D1) resides about 200 kb distal to the GWAS region. We hypothesized that circadian rhythms influenced gene expression levels in 17q12-q21 region and conversely, regulatory elements in this region influenced transcription of the core clock gene NR1D1 in cis. To test these hypotheses, we examined the diurnal expression profiles of zona pellucida binding protein 2 (ZPBP2/Zpbp2), gasdermin B (GSDMB), and ORMDL3/Ormdl3 in human and mouse tissues and analyzed the impact of genetic variation in the ZPBP2/Zpbp2 region on NR1D1/Nr1d1 expression. We found that Ormdl3 and Zpbp2 were controlled by the circadian clock in a tissue-specific fashion. We also report that deletion of the Zpbp2 region altered the expression profile of Nr1d1 in lungs and ileum in a time-dependent manner. In liver, the deletion was associated with enhanced expression of Ormdl3. We provide the first evidence that disease-associated genes Zpbp2 and Ormdl3 are regulated by circadian rhythms and the Zpbp2 region influences expression of the core clock gene Nr1d1.

Klíčová slova:

Asthma – Circadian rhythms – Gene expression – Gene regulation – Ileum – Transcriptional control – Circadian oscillators – Genetic oscillators


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Článek vyšel v časopise


2019 Číslo 9