Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)

Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) PIWI-interacting RNAs (piRNAs) are short RNAs of 24-31 nucleotides that are produced by cleavage of longer RNAs and amplification by a "ping-pong" mechanism involving rounds of strand hybridization and cleavage (reviewed in Sun et al. 2022). The piRNAs are loaded onto PIWI proteins (PIWIL1, PIWIL2, PIWIL4) that are then guided by base-pairing of the piRNAs to nascent and mature transcripts, where the PIWI:piRNA complexes initiate transcriptional and post-transcriptional silencing, respectively (reviewed in Czech et al. 2018, Onishi et al. 2021, Wang et al. 2023).
In mice, sources of piRNAs include transposon RNAs, long non-coding RNAs, exon transcripts, and RNAs from unannotated regions of the genome (Aravin et al. 2007, 2008). Two populations of piRNAs are observed during mouse development: pre-pachytene piRNAs and pachytene piRNAs (Aravin et al. 2008, Gan et al. 2011). Pre-pachytene piRNAs are present prenatally in prospermatogonial cells and postnatally in spermatogonial cells. Pachytene piRNAs are present in more mature postnatal spermatocytes and spermatids. The piRNAs derived from retroelements comprise about half (Aravin et al. 2008) or less (Gan et al. 2011) of the total pre-pachytene piRNAs and the portion falls sharply from pre-pachytene to pachytene (Gan et al. 2011).
In mice, PIWIL2 (MILI, Piwil2 gene) is first detected in primordial germ cells that have reached the genital ridge and expression persists through meiosis in adults. PIWIL4 (MIWI2, PIWIl4 gene) is present in mouse germ cells during de novo DNA methylation shortly before and after birth. PIWIL1 (MIWI, PIWIL1 gene) is present during later stages of meiosis after birth (Aravin et al. 2008). PIWIL4 and PIWIL2 participate in re-methylation of the genome in mouse germ cells and consequent repression of transposable elements (Carmell et al. 2007, Aravin et al. 2008, Kuramochi-Miyagawa et al. 2008, Zoch et al. 2020). In mice, the piRNAs bound by PIWIL4 bind nascent transcripts of transposable elements and connects to the de novo DNA methylation machinery via SPOCD1 and C19ORF84 to direct DNA methylation to the transposable elements (Zoch et al. 2020, 2024). Mutations in SPOCD1 are associated with infertility in men (Zoch et al. 2024)