Small ORFs as New Regulators of Pri-miRNAs and miRNAs Expression in Human and Drosophila

Abstract

MicroRNAs (miRNAs) are small regulatory non-coding RNAs, resulting from the cleavage of long primary transcripts (pri-miRNAs) in the nucleus by the Microprocessor complex generating precursors (pre-miRNAs) that are then exported to the cytoplasm and processed into mature miRNAs. Some miRNAs are hosted in pri-miRNAs annotated as long non-coding RNAs (lncRNAs) and defined as MIRHGs (for miRNA Host Genes). However, several lnc pri-miRNAs contain translatable small open reading frames (smORFs). If smORFs present within lncRNAs can encode functional small peptides, they can also constitute cis-regulatory elements involved in lncRNA decay. Here, we investigated the possible involvement of smORFs in the regulation of lnc pri-miRNAs in Human and Drosophila, focusing on pri-miRNAs previously shown to contain translatable smORFs. We show that smORFs regulate the expression levels of human pri-miR-155 and pri-miR-497, and Drosophila pri-miR-8 and pri-miR-14, and also affect the expression and activity of their associated miRNAs. This smORF-dependent regulation is independent of the nucleotidic and amino acidic sequences of the smORFs and is sensitive to the ribosome-stalling drug cycloheximide, suggesting the involvement of translational events. This study identifies smORFs as new cis-acting elements involved in the regulation of pri-miRNAs and miRNAs expression, in both Human and Drosophila melanogaster.

Noncoding RNA Regulation of Hormonal and Metabolic Systems in the Fruit Fly Drosophila

“…As mentioned previously, pri-miR-8 has been reported to encode for a small ORF that encodes for a miPEP-8, which can regulate the expression of hundreds more genes and will form a regulatory loop with miR-8 [ 182 ]. Similar ORFs have also been reported by other ncRNAs, such as lncRNA-MSA, miR-14 , and many more micro-peptides encoded in lncRNAs and circRNAs [ 145 , 183 , 184 ]. How miPEPs may have regulatory effects on the hormonal and metabolic systems and whether these miPEPs may also be regulatory targets for considerations of pathway disturbances such as insecticides all require further investigation in the future.…”

The Essentials on microRNA-Encoded Peptides from Plants to Animals

“…No common signature has been found among these different sORF-encoded peptides. However, so far, in plants, all tested miPEPs have been shown to act as an activator of their cognate miRNA expression contrasting with animals where only effects of sORF were detected [30,37,40].…”

“…miPEPs have been shown to act as an activator of their cognate miRNA expression contrasting with animals where only effects of sORF were detected [30,37,40].…”

RN7SL1 may be translated under oncogenic conditions

“…LINC01013 , a type of long intergenic ncRNA (lncRNA), contains smORF, and micropeptide translated from it was reported to activate myocardial fibroblasts ( 9 ). It was also reported that smORFs are also present in pri-miRNAs, which are precursors of microRNAs (miRNAs), and that smORFs regulate their expression levels in pri-miR-155 and pri-miR-497 ( 10 ). Although RN7SL1 theoretically possesses two smORFs encoding micropeptides of 7 and 16 amino acids from the 5′ side, their function is unknown.…”