Evolutionary Analysis of the hnRNP Interactomes and Their Functions in Eukaryotes

The heterogeneous nuclear ribonucleoproteins (hnRNPs) are central regulators of several fundamental biological processes across eukaryotes. hnRNPs have been implicated in transcriptional and post-transcriptional regulation, telomere maintenance, stem cell maintenance, among other processes in major model organisms. Though hnRNPs are known to be conserved in eukaryotes, the evolutionary conservation/diversification of their functions across species is yet to be understood. To this end, the present work employed computational analyses to identify potential hnRNP orthologs in eighty eukaryotic species, and their interactors. Subsequently, a comprehensive analysis of the biological processes influenced by hnRNP interactomes showed alternative splicing and splicing regulation to be commonly associated with most species, while a few processes were uniquely associated with particular species. Further studies of the clustering patterns of the top-ranking hub nodes of the hnRNP protein networks revealed a notable clustering pattern of hnRNP K orthologs from five species. Subsequent analysis of the genes with overrepresented hnRNP K target sites within their untranslated regions showed hnRNP K orthologs from humans and Ciona intestanilis to potentially target transcripts involved in membrane-related processes. Remarkably, the hnRNP K ortholog from Lottia gigantea was found to possibly regulate other RNA-binding proteins (RBPs), suggesting a regulatory cascade involving hnRNPs and other RBPs. Further experimental studies in this regard would be of scientific and clinical importance, owing to the druggability of several human hnRNPs.