Environmentally-Induced Transgenerational Epigenetic Inheritance: Implication of PIWI Interacting RNAs

Abstract

Environmentally-induced transgenerational epigenetic inheritance is an emerging field. The understanding of associated epigenetic mechanisms is currently in progress with open questions still remaining. In this review, we present an overview of the knowledge of environmentally-induced transgenerational inheritance and associated epigenetic mechanisms, mainly in animals. The second part focuses on the role of PIWI-interacting RNAs (piRNAs), a class of small RNAs involved in the maintenance of the germline genome, in epigenetic memory to put into perspective cases of environmentally-induced transgenerational inheritance involving piRNA production. Finally, the last part addresses how genomes are facing production of new piRNAs, and from a broader perspective, how this process might have consequences on evolution and on sporadic disease development.

Keywords: environment; piRNA; transgenerational epigenetics; transposable elements.

Figure 1

Germline PIWI-interacting RNAs (piRNA) biogenesis. In Drosophila melanogaster germ cells, active piRNA clusters are enriched in H3K9me3 and HP1-like protein Rhino (R), which interact with Deadlock (Del), Cutoff (Cuff). Moonshiner (Moon) interacts with Del and recruits transcription initiation factors, allowing transcription of piRNA clusters in the sense and antisense direction. Bootlegger, UAP56, the THO complex, Nxt1, Nxf3 are recruited to the piRNA cluster transcription site. The transcripts are then exported to the cytoplasmic piRNAs biogenesis site via the CRM1 exportin. In the cytoplasm, piRNA precursors are cleaved by Zucchini (Zuc) into primary piRNA and charged by Piwi or Aubergine (Aub) proteins, forming Piwi-piRISC and Aub-piRISC complexes. Piwi-piRISC is translocated into the nucleus and recognizes nascent TE transcripts due to the interaction with Panoramix, the Nxf2, and Nxt1. The association of these factors to nascent TE transcripts causes recruitment of the histone methyltransferase Eggless that transcriptionally silences TEs by local heterochromatinization. In the cytoplasm, Aub-piRISC cleaves TE transcripts into secondary piRNAs, which are loaded onto Ago3, forming Ago3-piRISC complexes. Ago3-piRISC recognizes and cleaves piRNA precursors into new secondary piRNAs, loaded onto Aub. This mechanism, known as the ‘Ping-Pong’ cycle, allows the amplification of piRISC complexes and post-transcriptional regulation of TEs.

Figure 2

The paramutation process in Drosophila melanogaster relies on maternal piRNA inheritance. At G0, females (grey chromosomes) carrying the BX2 clusters made of repeated P-lacZ-white transgenes (blue arrowheads) producing piRNAs are crossed to males (white chromosomes) carrying the same cluster not producing piRNA. At G1, maternal piRNA deposition in the embryo leads to activation of piRNA production from the paternal cluster allele. The newly activated cluster can activate the paternally-inherited inactive cluster in G2 due to maternal piRNA inheritance (MpI). Then, this process of activation leads to stable piRNAs production across generation.

Figure 3

Stable, heritable stress-induced de novo piRNAs. In flies, the BX2 cluster, a sequence made of repeated P-lacZ-white transgenes (dark blue arrowheads), is capable of producing piRNA after one generation at 29 °C, then these piRNAs can functionally repress a homologous P-lacZ sequence (light blue arrowheads) in trans. This silencing capacity is maintained at the second generation after return to normal temperature (25 °C) and then up to 50 generations. Hence, when stress is removed, piRNAs can be self-maintained by maternal piRNA inheritance (MpI) at each generation.