GSE98513
Suppression of asthmatic phenotype and altered lipid metabolism in mice lacking zona pellucida binding protein 2
The human chromosomal region 17q12-q21 is associated with childhood asthma.  It harbors 5 protein-coding genes, of which ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) and gasdermin B (GSDMB) are the top causal gene candidates.  Emerging evidence suggests that the promoter region of another gene, the zona pellucida binding protein 2 (ZPBP2), located more than 50kb proximal to ORMDL3 may be critical for its transcriptional regulation influencing susceptibility to asthma.  To test this hypothesis, we examined the lung phenotypes, liver transcriptomes and lipid metabolism of Zpbp2 knock-out (KO) mice. We found that in comparison to wild type (WT) mice, Zpbp2 KO mice sensitized with allergen ovalbumin (OVA) had reduced bronchial reactivity.  The Zpbp2 KO mice also had altered lipid metabolism with a 3-fold decrease in the levels of docosahexaenoic acid (DHA), increased body weight and changes in the expression of the adipocytokine signaling pathway gene peroxisome proliferator activated receptor alpha (Ppara).  The Zpbp2 deletion was also associated with increased DNA methylation at the Zpbp2 promoter/enhancer region, reminiscent of the methylation of the orthologous region in humans, and reduced expression of Ormdl3 in liver.  The sum of our results implies that the Zpbp2 gene is involved in the regulation of airway hypersensitivity and lipid metabolism, either directly or through a cis-regulatory effect on Ormdl3. Overall design: RNA-sequencing assays were conducted on RNA from livers of 3 C57BL/6J and 3 B6.Zpbp2-/- males.