Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion.

The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.

Identifying co-opted transposable elements using comparative epigenomics.

The human genome gives rise to different epigenomic landscapes that define each cell type and can be deregulated in disease. Recent efforts by ENCODE, the NIH Roadmap and the International Human Epigenome Consortium (IHEC) have made significant advances towards assembling reference epigenomic maps of various tissues. Notably, these projects have found that approximately 80% of human DNA was biochemically active in at least one epigenomic assay while only approximately 10% of the sequence displayed signs of purifying selection. Given that transposable elements (TEs) make up at least 50% of the human genome and can be actively transcribed or act as regulatory elements either for their own purposes or be co-opted for the benefit of their host; we are interested in exploring their overall contribution to the "functional" genome. Traditional methods used to identify functional DNA have relied on comparative genomics, conservation analysis and low throughput validation assays. To discover co-opted TEs, and distinguish them from noisy genomic elements, we argue that comparative epigenomic methods will also be important.