The amazing world of piRNAs : Biogenesis and function

By | April 27, 2021
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Piwi-interacting RNAs (piRNAs) play a significant role in all animals in safeguarding the germline from  random and lethal insertions of mobile DNA elements or Transposable elements (TEs). These piRNAs forms an important class of small non coding RNAs bearing some important differences compared to other members like microRNAs (miRNAs) and short interfering RNAs (siRNAs). As the name suggests,  these RNAs doesn’t code for any proteins as observed in the case of cellular mRNAs, which codes for protein upon translation.

piRNAs differs from other two class of non coding RNAs in biogenesis. The RNase III-enzyme Dicer produces small RNAs in both microRNA (miRNA) and RNA interference (RNAi) pathways whereas piRNAs are produced in dicer independent manner. miRNAs are genome-encoded, endogenous negative regulators of translation and mRNA stability originating from long primary transcripts with local hairpin structures. RNAi is triggered by the processing of long double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs), which mediate sequence-specific cleavage of nascent mRNAs.

All three classes of small non coding RNAs interact with specific proteins called as the Argonaute proteins.In case of short RNAs (siRNAs) form the RNA-induced silencing complexes termed (RISCs) and in the case of miRNAs this complex is referred to as miRISC. piRNAs forms a complex with piwi class of Argonaute proteins(Aubergine, Piwi and Ago3 in Drosophila) and these proteins can be phylogenetically separated into two clades based on sequence similarity: the Ago clade and the Piwi (P-element induced wimpy testis) clade.

Unlike miRNAs which are evolutionary conserved, piRNAs display surprisingly diverse sequences between different organisms, even between closely related species. However piRNAs among various animals share some important similarities:
1) piRNAs in Drosophila are between 26 and 30 nucleotides (nt) in length, have a ‘preference’ for a 5′ uracil, and posses a 3′-most sugar that is 2′-O-methylated.
2) In c.elegans piRNAs are 21 nt long but share the 5′ and 3′ features of piRNAs exhibited by other organisms.

Biogenesis of piRNAs is not completely understood but however few things are clear related to piRNAs generation. The biogenesis of piRNAs differ significantly in different animals : Immature piRNAs arise from specific genomic cluster mostly localized in pericentomeric region which are transcribed uni/bi directionnaly in long single-stranded RNA precursors by the RNA polymerase II . In another mechanism, which occurs in the cytoplasm, two other Piwi proteins, AUB and AGO3 upon loaded with piRNAs leads to cleavage and destruction homologous transposon transcripts using their endonuclease activity.This cleavage of complementary transcripts by AUB and AGO3 also leads to the generation of new piRNAs ,termed as ping pong mechanism .The ping-pong pathway in Drosophila is initiated  by both maternally deposited piRNAs through germline transmission and zygotic primary piRNAs that are antisense to TEs and loaded onto Aub. Ping-pong signatures have been identified in very primitive animals such as sponges and cnidarians, pointing to the existence of the ping-pong cycle already in the early branches of metazoans. As mentioned above the exact mechanism for piRNA biogensis is not known, but involvement of following proteins is crucial for generation of piRNAs:
Ago3, Aubergine, Piwi, Armitage, Spindle-E , Zucchini, Tudor, Yb, Tejas, Vasa, Maelstrom, SETDB1, cutoff, Rhino ,SuVar3-9 and Deadlock.

Functions of piRNAs:
The wide variation in piRNA sequences among species contributes to the difficulty in understanding the specificity and functionality of piRNAs. The best known and better understood function of piRNAs is its role in post-transcriptional transposon repression.TEs happen to be prominent targets of piRNAs and via ping ping cycle in which a transposon target is recognised by a piRNA and sliced by the Piwi protein through its slicer activity giving rise to new piRNA with opposite orientation and also cleaving (hence silencing) TEs transcripts.

Evidence from sequencing of different organisms has identified loads of piRNAs that do not readily match to transposons or repetitive pseudogenes indicating that there is more to piRNA function apart from its vital and well studied role in silencing repeat elements. In support of this argument Martine Simonelig lab in France, using nanos maternal mRNAs degradation as a reference, have shown that piRNAs derived from transposon can target protein-coding mRNAs by binding directly to sequence in 3’UTR. The study demonstrates that complex of piRNAs, Piwi proteins ( Aubergine / Ago3) and CCR4-NOT deadenylation complex is responsible for degradation of maternal nos mRNA in the majority of the embryo. This work was supported by another work published in cell research where authors demonstrates involvement of pachytene piRNAs in instructing massive mRNA elimination in mouse elongating spermatids.

Further reading:
1) piRNAs: from biogenesis to function.
Weick EM, Miska EA.
Development. 2014 Sep;141(18):3458-3471.

2) Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis
Gou LT, Dai P, Yang JH et al.
Cell Res. 2014 Jun;24(6):680-700. doi: 10.1038/cr.2014.41. Epub 2014 May 2.

3) Maternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo.
Rouget C, Papin C, Boureux A, Meunier AC, Franco B, Robine N, Lai EC, Pelisson A, Simonelig M.
Nature. 2010 Oct 28;467(7319):1128-32. doi: 10.1038/nature09465. Epub 2010 Oct 17.

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