Neuropeptide Receptors Harbor More Genomic Regulatory Elements in Their Loci Than the Loci of Their Ligands

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. To elucidate the underlying mechanisms of this expression pattern divergence, here we dissect the genomic and epigenomic architectures of these two distinct gene classes. 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 transcripts. 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. Furthermore, the increased length of NPR transcripts was driven by longer exons rather than higher exon counts. Consistently, the number of spliced variants per gene was similar between NPs and NPRs, suggesting that alternative splicing events are a minor contributor to their distinct expression patterns. At the RNA level, NPR mRNAs possess significantly longer 3'UTRs compared to NPs, indicating a greater potential for post-transcriptional gene regulation. This complexity is also mirrored at the chromatin level, where NPR loci exhibit a higher density of epigenetic marks than NPs. Together, these findings highlight the multi-layered nature of gene regulation prioritizing control at the receptor level.