The antisense piRNAs by the cleavage of antisense piRNA

The main distribution sites piRNA are the animal testesspermatogonial cells and ovarian oocytes and in drosophila follicle cells (somaticcells).

There are two main models for the piRNA biogenesis: In germ cells, the AUBdependent piRNA pathway (secondary piRNA processing) is active, while in somaticcells, only pathway for producing piRNAs is the PIWI_dependent pathway (primarypiRNA processing) (15). The primary antisense transcripts of piRNA arepreferably loaded onto PIWI protein. This complex is called as piRISCs(piRNA-induced silencing complexes) which breaks the sense transcript of transposonsat positions 10 and 11 and generate the 5′ end of a sense Ago3-associatedpiRNA. In the AUB dependent pathway that is known as the Ping-Pong cycle,proteins of AUB and Argonaute 3 (AGO3) are involved (16).

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The AUB protein plays a similar role to PIWI andforms the 5? end of piRNAs that associated with AGO3. This complex produces the5? end of the antisense piRNAs by the cleavage of antisense piRNA precursorsand then these are loaded onto AUB (17). The HEN1 protein mediated 2??O-methylationof the 3? end of piRNA. Also, Mili and Miwi2 are two members of the mouse Piwiproteins that by processing of transposable elements (TEs) produce piRNAs. Thisoccurs in cytoplasmic granules called pi-bodies and piP-bodies (18).  The role of piRNAs in male infertility The piRNAs can play differentroles in biological processes, including: Gene Silencing, Epigenetic Regulation, SexDetermination, and Cancer. Their most important role is toprotect the gametes genome from the transposon invasion and is performed byPIWI-piRNA complexes with silencing their transcripts (17). Consequently, piRNAs are usually used in the genome,but the aberrant expression of each of the genes involved in biogenesis andfunction can lead to modifications in the genome and different disorders.

 One of these disorders is male infertility. In Figure 1, the most important research performed onmale infertility and piRNAs is summarized:The Moloney leukemia virus 10-like 1 (MOV10L1) gene isa piRNA biogenesis-associated gene that plays a role in the primary and secondaryprocessing (19). It can help primary piRNAs for binding to the PIWIprotein. Studies have confirmed that several polymorphisms of this gene have asignificant increase in infertile males (20). In human, the association of four human PIWI proteins(HIWI, HILI, HIWI2 and PIWIL3) in male fertility has been shown.

In 2010 and2017, investigations on Chinese and Iranian populations with non-obstructiveazoospermia revealed independently a relationship between HIWI2 rs508485 (T>C)and non-obstructive azoospermia and this variant can be considered as a riskfactor for male infertility (21, 22).A recent study onperipheral blood samples of 30 infertile men, showedthat rs10773767 and rs6982089 were two single nucleotidepolymorphisms (SNPs) in PIWIL1 andPIWIL2 respectively. These polymorphisms were allele-specificmethylation-sensitive and suggests that DNA methylation changes in these genesare associated with spermatogenesis disorders (23). Furthermore, Transposons are repetitive elements thatuse the genome of a host cell to survive and amplification. For protecting ofthe genomes of gametes from their invasion, PIWI-piRNA complexes target them tosilence of their transcripts.

LINE-1 (L1) is one of the transposons studiedthat by performing the examinations on patients with cryptorchidism revealed thata consequence of alterations in the Piwi-pathway and derepression oftransposable elements in these patients is infertility (24). These studies indicate that piRNAs may play a crucial role in male infertility.