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

Area of Science:

• Genetics
• Chronobiology
• Immunology

Background:

• Immunity-mediated diseases share genetic associations in the 17q12-q21 chromosomal region.
• ORMDL3 is a key candidate gene, but disease associations are complex, potentially involving circadian rhythm influences.
• Circadian rhythm dysregulation is linked to chronic inflammatory diseases, yet its role in 17q12-q21 gene regulation is unexplored.

Purpose of the Study:

• To investigate the influence of circadian rhythms on gene expression within the 17q12-q21 region.
• To determine if regulatory elements in the 17q12-q21 region affect the core clock gene NR1D1.
• To explore the interplay between circadian rhythms and disease-associated genes in this locus.

Main Methods:

• Examined diurnal expression profiles of ZPBP2, GSDMB, and ORMDL3 in human and mouse tissues.
• Analyzed the impact of genetic variation in the ZPBP2 region on NR1D1 expression.
• Utilized tissue-specific expression analysis and genetic deletion models.

Main Results:

• ORMDL3 and ZPBP2 exhibit tissue-specific circadian clock control.
• Deletion of the ZPBP2 region altered NR1D1 expression profiles in lungs and ileum in a time-dependent manner.
• Liver-specific deletion of the ZPBP2 region enhanced ORMDL3 expression.

Conclusions:

• Provides the first evidence that ZPBP2 and ORMDL3 are regulated by circadian rhythms.
• Demonstrates that the ZPBP2 region influences the expression of the core clock gene NR1D1.
• Suggests a novel link between circadian regulation, the 17q12-q21 locus, and immune-mediated diseases.