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PIWI-interacting RNAs (piRNAs) are a class of small noncoding RNAs bound to PIWI proteins. PIWI-interacting RNAs are abundantly expressed in the germ line, and are essential for spermatogenesis in mammals [1]. In adult mouse testes, the majority of piRNAs start to express in pachytene spermatocytes and are therefore called pachytene piRNAs. Pachytene piRNAs are depleted of transposable elements (TEs)-derived sequences, and are mostly derived from autosomal intergenic piRNA producing loci [2]. Driven by the transcription factor A-MYB, RNA polymerase II synthesizes pachytene piRNA precursors, which are further processed into 24– 32 nt mature piRNAs [3]. Unlike piRNAs expressed in primordial germ cells, most of the pachytene piRNAs are not generated through the typical ping-pong amplification mechanism [4]. Unlike miRNAs or siRNAs whose production can be predicted based on the secondary structure or sequence conservation, piRNAs are defined solely by their associations with PIWI proteins. Principles that define which sequences become piRNAs remain unknown; however, new factors involved in primary piRNA processing are constantly emerging. Several Tudor domain proteins (TDRD1, 2, 4, 9, and 12) have been shown to play a critical role in piRNA biogenesis by binding to PIWI proteins using their Tudor domains at arginine methylation sites and/or arginine-rich sequences [5–6]. A recent report by Dr Chen Chen’s group has uncovered the function of another Tudor domain protein, TDRD5, in piRNA biogenesis [7]. TDRD5 interacts with MIWI and MILI, two mouse PIWI proteins that both associate with pachytene piRNAs. By conditional inactivation of Tdrd5 in postnatal male germ cells in mice (Tdrd5cKO), the authors show that spermatogenesis is arrested at the round spermatid stage, and the testes of Tdrd5cKO mice are about half the weight of wildtype controls. Sequencing analyses on mouse testicular small RNAs reveal that the piRNA levels in Tdrd5cKO testes are ∼25–30% of the wild-type controls. Further analyses reveal that it is the MIWIbound piRNAs (29–32 nt), but not MILI-bound ones (25–28 nt) that are reduced significantly in Tdrd5cKO testes, suggesting a severe loss of bulk pachytene piRNAs. Surprisingly, pachytene piRNA production is not uniformly decreased across the entire length of piRNA precursors in Tdrd5cKO spermatogenic cells. The near-5′-end portions (the first ∼300 nt) of piRNA precursors produce a comparable amount piRNAs, but the downstream portions yield much fewer piRNAs and thus, contribute to the overall piRNA loss. Crosslinking immunoprecipitation assays uncover that TDRD5 binds the entire length, rather than the very 5′ portions, of the piRNA precursors. Quantitative PCR analyses indicate that piRNA precursors do not accumulate in Tdrd5cKO male germ cells. Together, these data suggest a previously unrecognized biphasic processing of piRNA precursors: the near 5′-end processing and the downstream processing (Figure 1). Despite the common belief that most, if not all, of the piRNA biogenic factors uniformly affect the production of all piRNAs from a piRNA precursor, this study surprises us by demonstrating that the processing of piRNAs from the very 5′ portions of the piRNA precursors can be genetically separated from that of downstream piRNAs. This finding not only supports a model of stepwise processing (Figure 1), but also suggests that piRNA biogenesis pathways are far more complex than we previously expected.

Disruption ofTdrd5decouples the stepwise processing of long precursor transcripts during pachytene PIWI-interacting RNA biogenesis