Syntenic lncRNA locus exhibits DNA regulatory functions with sequence evolution.

Syntenic long non-coding RNAs (lncRNAs) often show limited sequence conservation across species, prompting concern in the field. This study delves into functional signatures of syntenic lncRNAs between humans and zebrafish. Syntenic lncRNAs are highly expressed in zebrafish, with ∼90 % located near protein-coding genes, either in sense or antisense orientation. During early zebrafish development and in human embryonic stem cells (H1-hESC), syntenic lncRNA loci are enriched with cis-regulatory repressor signatures, influencing the expression of development-associated genes. In later zebrafish developmental stages and specific human cell lines, these syntenic lncRNA loci function as enhancers or transcription start sites (TSS) for protein-coding genes. Analysis of transposable elements (TEs) in syntenic lncRNA sequences revealed intriguing patterns: human lncRNAs are enriched in simple repeat elements, while their zebrafish counterparts show enrichment in LTR elements. This sequence evolution likely arises from post-rearrangement mutations that enhance DNA elements or cis-regulatory functions. It may also contribute to vertebrate innovation by creating novel transcription factor binding sites within the locus. This study highlights the conserved functionality of syntenic lncRNA loci through DNA elements, emphasizing their conserved roles across species despite sequence divergence.