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The histone demethylase KDM3 prevents auto-immune piRNAs production in Drosophila

ABSTRACT: In animals, genome integrity of the germ line is protected from transposable element (TE) activity by small, non-coding, dedicated RNAs acting as an immune system against TEs, and called PIWI-interacting RNAs (piRNAs) (Czech et al. 2018, Ozata et al. 2018). In Drosophila, the production of piRNAs is initiated from heterochromatic loci containing remnants of TEs and enriched in histone H3 trimethylated on lysine 9 (H3K9me3) (Brennecke et al. 2007, Gunarwardane et al. 2007; Rangan et al. 2011). These loci, called piRNA clusters, constitute a memory of past TE invasions. Little is known about how piRNA clusters are genetically defined. Using a genetic screen combined with a bimodal epigenetic state piRNA cluster (BX2), we identified the splicing factor Half pint (Hfp) and the histone demethylase KDM3 as being able to prevent BX2 piRNA production. Furthermore, we showed that Hfp is needed to splice Kdm3 transcripts. Germline expression of Kdm3 coding sequence (splicing-independent) rescued the hfp germline knock-down (GLKD) effect demonstrating that Kdm3 is sufficient to prevent BX2 piRNA production. Our data revealed that in the absence of Kdm3, dozens of gene-containing regions become bona fide germinal dual strand piRNA clusters. Indeed, they produce piRNAs originating from both DNA strands, become transcribed in a Moonshiner-dependent manner and enriched in di-and tri-methylation of lysine 9 of histone H3 (H3K9me2/3) and in Rhino, an HP1-like protein. Eggs laid by Kdm3 GLKD females do not hatch and show developmental defects phenocopying loss of function of genes included into the new piRNA clusters, suggesting an inheritance of functional ovarian “auto-immune” piRNAs. Our results demonstrate that some gene-containing regions are actively prevented for piRNA production by proteins that counteract piRNA cluster emergence. Hence, a non-piRNA-producing state is therefore not a "by default" state but rather a cellular lock that is actively controlled for some genomic loci.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE203279 | GEO | 2023/02/07

REPOSITORIES: GEO

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Project description:Small non-coding RNAs that associate with Piwi proteins, called piRNAs, serve as guides for repression of diverse transposable elements in germ cells of Metazoa. In Drosophila, the genomic regions that give rise to piRNAs, the so-called piRNA clusters, are transcribed to generate long precursor molecules that are processed into mature piRNAs. How genomic regions that give rise to piRNA precursor transcripts are differentiated from the rest of the genome and how these transcripts are specifically channeled into the piRNA biogenesis pathway are not known. We found that trans-generationally inherited piRNAs provide the critical trigger for piRNA production from homologous genomic regions in the next generation by two different mechanisms. First, inherited piRNAs enhance processing of homologous transcripts into mature piRNAs by initiating the ping-pong cycle in the cytoplasm. Second, inherited piRNAs induce installment of the H3K9me3 mark on genomic piRNA cluster sequences. The HP1 homolog Rhino binds to the H3K9me3 mark through its chromodomain and is enriched over piRNA clusters. Rhino recruits the piRNA biogenesis factor Cutoff to piRNA clusters and is required for efficient transcription of piRNA precursors. We propose that trans-generationally inherited piRNAs act as an epigenetic memory for identification of substrates for piRNA biogenesis on two levels, by inducing a permissive chromatin environment for piRNA precursor synthesis and by enhancing processing of these precursors. sequencing of argonaute-bound and total small RNAs from ovaries of different fly crosses: maternal deposition (MD) crosses, in which piRNAs from the P1152 locus are transmitted into the next generation through the mother. No maternak deposition (NMD) crosses, which are reciprocal to the MD crosses. Subsequently, no piRNAs from the P1152 locus are transmitted into the next generation. The strain P-1152, that carries insertion of P{lArB} construct in telomeric sequences of X chromosome (site 1A) is described in (Roche and Rio 1998). The strain BC69 that has insertion of P{A92} construct at a euchromatic location on chromosome 2L (site 35B10-35C1) is described in (Lemaitre et al. 1993).Both stocks were a generous gift from S. Ronsseray.

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The histone demethylase KDM3 prevents auto-immune piRNAs production in Drosophila

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