Motif conservation, stability, and host gene expression are the main drivers of snoRNA expression across vertebrates

Abstract

Small nucleolar RNAs (snoRNAs) are structured noncoding RNAs present in multiple copies within eukaryotic genomes. SnoRNAs guide chemical modifications on their target RNA and regulate processes like ribosome assembly and splicing. Most human snoRNAs are embedded within host gene introns, the remainder being independently expressed from intergenic regions. We recently characterized the abundance of snoRNAs and their host gene across several healthy human tissues and found that the level of most snoRNAs does not correlate with that of their host gene, with the observation that snoRNAs embedded within the same host gene often differ drastically in abundance. To better understand the determinants of snoRNA expression, we trained machine learning models to predict whether snoRNAs are expressed or not in human tissues based on more than 30 collected features related to snoRNAs and their genomic context. By interpreting the models' predictions, we find that snoRNAs rely on conserved motifs, a stable global structure and terminal stem, and on a transcribed locus to be expressed. We observe that these features explain well the varying abundance of snoRNAs embedded within the same host gene. By predicting the expression status of snoRNAs across several vertebrates, we notice that only 1/3 of all annotated snoRNAs are expressed per genome, as in human. Our results suggest that ancestral snoRNAs disseminated within vertebrate genomes, sometimes leading to the development of new functions and a probable gain in fitness, thereby conserving features favorable to the expression of these few snoRNAs, the large remainder often degenerating into pseudogenes.

Comprehensive map of ribosomal 2′-O-methylation and C/D box snoRNAs inDrosophila melanogaster

“…Instead they could be classified as pseudogene (Figure 3A). This is supported by the fact that host gene expression is a positive indicator of intronic snoRNA expression, which is the opposite in the case of 34 out of the 37 non expressed snoRNAs whose respective host gene is expressed (50). Finally, our de novo search for non-annotated snoRNAs yielded only one hit, snoCD45, but we cannot exclude that future tools or different parameters could reveal new C/D box snoRNAs in D. melanogaster.…”

Maturation of small nucleolar RNAs: from production to function

“…Much of the discrepancy in expression of snoRNAs and their host genes can be explained by known mechanisms of RNA regulation [ 48 ] including NMD [ 64 ], dual initiation promoters [ 56 ] and alternative processing of snoRNAs [ 65 ]. A recent computational study showed that motif conservation, overall snoRNA stability, formation of terminal stem and the host gene expression serve as main predictors of snoRNA expression [ 66 ]. Although it is evident that the genomic organization of a snoRNA dictates its maturation path, it remains unclear to what extent a snoRNA’s pathway to maturity influences its abundance and function.…”