Evidence That Regulation of Pri-miRNA/miRNA Expression Is Not a General Rule of miPEPs Function in Humans

Abstract

Some miRNAs are located in RNA precursors (pri-miRNAs) annotated as long non-coding (lncRNAs) due to absence of long open reading frames (ORFs). However, recent studies have shown that some lnc pri-miRNAs encode peptides called miPEPs (miRNA-encoded peptides). Initially discovered in plants, three miPEPs have also been identified in humans. Herein, we found that a dozen human pri-miRNAs potentially encode miPEPs, as revealed by ribosome profiling and proteomic databases survey. So far, the only known function of plant miPEPs is to enhance the transcription of their own pri-miRNAs, thereby increasing the level and activity of their associated miRNAs and downregulating the expression of their target genes. To date, in humans, only miPEP133 was shown to promote a positive autoregulatory loop. We investigated whether other human miPEPs are also involved in regulating the expression of their miRNAs by studying miPEP155, encoded by the lnc MIR155HG, miPEP497, a sORF-encoded peptide within lnc MIR497HG, and miPEP200a, encoded by the pri-miRNA of miR-200a/miR-200b. We show that overexpression of these miPEPs is unable to impact the expression/activity of their own pri-miRNA/miRNAs in humans, indicating that the positive feedback regulation observed with plant miPEPs and human miPEP133 is not a general rule of human miPEP function.

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

“…Analyses of the Human and Drosophila lnc pri-miRNAs with ribosome profiling databases [ 35 ] reveal that several of them harbor smORFs exhibiting ribosome translation marks [ 36 , 37 ]. Moreover, a few of them have been shown to encode functional peptides [ 36 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

“…Here, we questioned the possible involvement of smORFs in the regulation of lnc pri-miRNAs in Human and Drosophila melanogaster . We focused on Human pri-miR-155, pri-miR-497 and Drosophila pri-miR8 since we have previously shown that these pri-miRNAs contain translatable smORFs [ 36 , 37 , 42 ]. We found that smORFs regulate the expression levels of human pri-miR-155, pri-miR-497 and Drosophila pri-miR-8 and pri-miR-14.…”

Functions of animal microRNA‐encoded peptides: the race is on!

“…miPEPs encoded by the lncRNAs pri‐miR‐22 (Razooky et al , 2017), pri‐miR‐155 (Niu et al , 2020), pri‐miR‐34a (Kang et al , 2020) and pri‐miR‐147b (C15ORF48) (Lee et al , 2021) were first identified in humans, by pri‐miR‐8 and the pri‐miR‐msa in Drosophila . Prel et al (2021) performed a survey of the 48 Human lnc miRNA host genes (MIRHGs) revealing that 32 pri‐miRNAs (including pri‐miR‐31) contain sORFs exhibiting ribosome profiling marks (Prel et al , 2021). Amongst them, 22 peptides were identified by mass spectrometry and reported in OpenProt (http://www.openprot.org), an online database of translated sORFs (Bruet et al , 2021).…”

“…experiments performed in THP‐1‐derived dendritic cells treated with miPEP155 showed that pri‐miR‐155 expression is not affected by miPEP155 treatment (Niu et al , 2020). Additionally, overexpression of miPEP155 in Hela cells has no impact on the expression of pri‐miR‐155 and on the activity of miR‐155, suggesting that miPEP155 does not regulate its own expression (Niu et al , 2020; Prel et al , 2021). Moreover, miPEP155 has an antagonistic effect on miR‐155.…”

“…Moreover, miPEP155 has an antagonistic effect on miR‐155. It exerts an anti‐inflammatory role (Niu et al , 2020), while miR‐155 mediates inflammation and immune responses, and miPEP155 overexpression in Hela cells increases Rictor and EGFR expression, while miR‐155 overexpression represses these genes (Prel et al , 2021).…”