Differential genomic architecture of a ligand-receptor pair in humans and commonly used model organisms

The neuropeptide signaling pathway is vital for the physiology and behavior of multicellular organisms. This pathway is mediated by ligand-receptor binding, wherein neuropeptides (NPs) are often released from neurons, while their receptors (NPRs) are ubiquitously expressed in both neuronal and non-neuronal cell types. Yet, the underlying mechanisms driving these divergent expression patterns remain unidentified. To address this, we dissect the genomic and epigenomic architectures of these two gene classes using the most up-to-date and comprehensive list of NP and NPR genes identified so far.

We first characterized the genomic architecture of NP and NPR genes to compare their total gene length, exon and intron lengths, exon counts, and number of alternatively spliced transcripts per gene. We also profiled their regulatory genomic elements including CpG islands, TATA boxes, and their overlapping antisense RNAs. These analyses were then expanded to non-human model organisms to evaluate the evolutionary conservation of the underlying mechanisms.

We found that NPRs encompass larger genomic loci and encode longer transcripts than NPs. We also found that the increased length of NPR transcripts was driven by longer exons rather than higher exon counts. The number of alternatively spliced variants per gene was similar between NPs and NPRs, suggesting that alternative splicing is a minor contributor to the distinct expression patterns of NP and NPR genes. Introns-genomic regions with varied range of regulatory elements-were drastically longer in NPR loci than in NPs. Consistent with these findings, NPR genes exhibited a higher density of epigenetic marks in their genomic loci than NPs. At the RNA level, NPR mRNAs possess significantly longer 3'UTRs compared to NPs, indicating a greater potential for post-transcriptional gene regulation, such as microRNA binding capability.

Taken together, these findings highlight the primacy of genomic and epigenomic regulatory mechanisms in the neuropeptide signaling pathways at the 'receptor' level. Future studies can apply a similar approach to other ligand-receptor pairs to generalize and expand the conceptual framework presented here.