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Aravin, A. A.

Publications and source records attributed to Aravin, A. A..

15 recordsLinked to original sources

piRNA loss unleashes episodic transposition bursts

In Metazoa, transposon expression is suppressed by the piRNA pathway, and disruption of this pathway leads to rampant transposon expression. However, it remains unclear whether increased transposon expression results in actual transposition, and if so, which and how frequently transposons mobilize upon piRNA loss. Here, we developed a framework to track transposon copy accumulation across generations on a single set of nonrecombining haploid genome in the Drosophila male germline, with or without the piRNA biogenesis factor HP1D/Rhino. Single-fly Nanopore DNA sequencing revealed that multiple transposon families mobilized after 10-45 generations of piRNA loss. Among them, the most prolific across all replicates was copia, producing dozens of new insertions that were distributed across chromosome arms. With genomic DNA collected at every generation, we validated and dated each copia insertion, revealing episodic bursts of transposition that deviated strongly from a Poisson process. Using phylogenetic analysis, we further showed that multiple copia loci--both autonomous and nonautonomous copies--can mobilize. Interestingly, two additional transposon families, mdg3 and invader3, also mobilized episodically, but with distinct timing and magnitude, highlighting the stochastic nature of transposition bursts. Because we did not observe a single transposition event for these elements in controls, our results provide direct evidence that the piRNA pathway tightly suppresses germline transposition. More importantly, our findings argue that disruption of the piRNA pathway does not simply elevate transposition rates, but it instead unleashes punctuated and stochastic bursts of transposon movement that may radically reshape the timing and magnitude of mutational input during evolution.

genetics↗

Tetramerization and RNA-guided filament assembly control Schlafen-Argonaute antiphage defense

Two deeply conserved protein families, Argonaute (Ago) and Schlafen (SLFN), play defense roles in diverse prokaryotes and eukaryotes, including humans. Here, we identify a monophyletic group of proteins broadly distributed across bacteria and archaea that fuse a SLFN domain with an Ago core and a GHKL-family ATPase. Using SLFN-pAgo from Runella zeae as a model, we show that these proteins protect bacterial cells against bacteriophages by employing the Ago core as a guide-dependent sensor and the SLFN domain as a nuclease effector to induce abortive infection via tRNAs cleavage. Structural and biochemical analyses reveal that ATP binding by the GHKL domain drives tetramerization of SLFN-pAgo, reconstituting the canonical SLFN nuclease architecture found in mammalian proteins. Prior to target detection, non-canonical guide RNA binding induces the formation of long helical filaments, locking the SLFN domains in an inactive configuration. Guide-dependent recognition of complementary target DNA triggers massive structural rearrangements leading to filament disassembly and the induction of SLFN nuclease activity. Together, our findings uncover a new antiphage system that employs reversible guide- and ATP-mediated oligomerization to strictly regulate cooperation between an Ago sensor and a SLFN RNAse effector.

molecular biology↗

piRNA direct the chromatin reader to its genomic targets

The chromatin reader Rhino (Rhi) is an HP1-paralog and master regulator of piRNA biogenesis in Drosophila that drives the transcription of piRNA precursors. While Rhi binds the heterochromatic mark H3K9me3, this interaction is insufficient to explain its specific occupancy, as Rhi is excluded from the majority of H3K9me3-enriched loci. Instead, we find that Rhi recruitment is orchestrated by several competing pathways, including the piRNA-guided protein Panoramix (Panx) and the DNA-binding protein Kipferl (Kipf). We demonstrate that Panx functions as a piRNA-guided modular scaffold that directs Rhi to its targets through a dual-mode mechanism: its N-terminus recruits the H3K9 methyltransferase machinery, while its C-terminus directly binds the Rhi chromodomain. While H3K9me3 deposition provides a necessary foundation, it acts in synergy with the direct Panx-Rhi physical bridge to drive robust Rhi occupancy. Furthermore, Rhi recruitment is amplified by the cytoplasmic inheritance of maternal piRNAs, forming a transgenerational feed-forward loop. Our results reveal that the piRNA pathway imparts sequence-specificity to the H3K9me3 code, utilizing a direct physical bridge to program the genomic distribution of the chromatin reader Rhi.

molecular biology↗

A trans-piRNA network and transcriptional antagonism shape piRNA cluster function

PIWI-interacting (pi)RNAs protect animal germlines from transposable elements (TEs) by guiding their sequence-specific repression. In Drosophila germline, piRNAs are encoded in distinct genomic regions, piRNA clusters (piCs), that are transcribed by a non-canonical machinery that is anchored on chromatin by the HP1 paralogue Rhino. Studies of transgenic piCs revealed that piRNA biogenesis depends on cytoplasmic inheritance of piRNAs, however, whether native piCs require trans-generational piRNA transmission remained unknown. Here, we used two approaches to show that cytoplasmic inheritance of cognate piRNAs is critical for piRNA biogenesis. Our analyses reveal that individual piCs form a tightly interconnected network linked by trans-acting piRNAs that reinforce biogenesis. According to the transposon trap model, the content of piCs is updated by integration of novel TEs leading to production of piRNA guides against integrated transposons. However, we found that transcription driven by promoters integrated into piCs disrupt local piRNA biogenesis by removing Rhino and antagonizing non-canonical transcription of piRNA precursors. Thus, newly inserted transposons might suppress piRNA production before they become domesticated by the piRNA pathway calling for a revision of the trap model. Together, our results reveal that piC activity is shaped by transcriptional competition and a dynamic interplay between individual piCs connected into a common network. HighlightsO_LICytoplasmic inheritance of maternal piRNAs is required for piRNA biogenesis in the next generation C_LIO_LITrans-acting piRNA ensure robustness of piRNA biogenesis and repression by connecting individual clusters into a functional network C_LIO_LIPing-pong amplification provides non-uniform processing of different regions inside piCs C_LIO_LIGenes can remain active inside piRNA clusters antagonizing Rhino-dependent non-canonical transcription and piRNA biogenesis, challenging the transposon trap model C_LI

molecular biology↗

Auto-methylation of the histone methyltransferase SetDB1 at its histone-mimic motifs ensures the spreading and maintenance of heterochromatin

Heterochromatin plays a critical role in nuclear organization and the regulation of gene expression by directing 3D genome organization, regulating lineage-specific gene expression, and ensuring the repression of transposable elements and endogenous retroviruses. Functionally and structurally distinct chromatin domains are defined by the so-called histone code, which consists of combinations of post-translational histone modifications deposited by "code writers" and recognized by "code readers." The primary mark of heterochromatin, trimethylation of histone H3 at lysine 9 (H3K9me3), is deposited by histone methyltransferases, such as SetDB1, and serves as a binding platform for readers, most notably HP1 family proteins. Using a reporter system to monitor the dynamics of heterochromatin establishment and maintenance, we demonstrated that transient tethering of HP1 triggers the SetDB1-dependent establishment of stable heterochromatin. This finding indicates the presence of a feedback mechanism wherein the reader of the H3K9me3 mark recruits the writer. We further discovered that the genetic interaction between SetDB1 and HP1 is mirrored by a direct physical interaction. This interaction requires the auto-methylation of two conserved histone mimic motifs located in unstructured regions of SetDB1. HP1 binds these SetDB1 motifs using the same molecular interface it employs to recognize the modified histone tail. Our findings show that SetDB1 auto-methylation is essential for the spreading and stable maintenance of heterochromatin. This includes its roles in processes such as X-chromosome inactivation and the negative feedback regulation of a large gene family encoding KRAB-ZNF transcriptional repressors. Thus, the primary heterochromatin mark is not limited to nucleosomes but is also deployed on the marks writer itself. This fosters a direct physical interaction between the writer and the reader, ensuring key features of heterochromatin: its spreading to establish extended domains and its stable maintenance through cell divisions.

genetics↗

Escalation of genome defense capacity enables control of an expanding meiotic driver

SummaryFrom RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity1,2. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, which controls selfish elements in the metazoan germline, diverse target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases via enzymatic cleavage1,3. Such a binary architecture allows the defense systems to be readily adaptable, where new targets can be captured via the innovation of new specificity factors4,5. Thus, our current understanding of genome defense against lineage-specific selfish genes has been largely limited to the evolution of specificity factors, while it remains poorly understood whether other types of innovations are required. Here, we describe a new type of innovation, which escalates the defense capacity of the piRNA pathway to control a recently expanded selfish gene in Drosophila melanogaster. Through an in vivo RNAi screen for repressors of Stellate--a recently evolved and expanded selfish meiotic driver6-8--we discovered a novel defense factor, Trailblazer. Trailblazer is a transcription factor that promotes the expression of two PIWI-clade nucleases, Aub and AGO3, to match Stellate in abundance. Recent innovation in the DNA-binding domain of Trailblazer enabled it to drastically elevate Aub and AGO3 expression in the D. melanogaster lineage, thereby escalating the silencing capacity of the piRNA pathway to control expanded Stellate and safeguard fertility. As copy-number expansion is a recurrent feature of diverse selfish genes across the tree of life9-12, we envision that augmenting the defense capacity to quantitatively match selfish genes is likely a repeatedly employed defense strategy in evolution.

genetics↗

Genetic control of a sex-specific piRNA program

Sexually dimorphic traits in morphologies are widely studied, but those in essential molecular pathways remain largely unexplored. Previous work showed substantial sex differences in Drosophila gonadal piRNAs, which guide PIWI proteins to silence selfish genetic elements thereby safeguarding fertility. However, the genetic control mechanisms of piRNA sexual dimorphism remain unknown. Here, we showed that most sex differences in the piRNA program originate from the germline rather than gonadal somatic cells. Building on this, we dissected the contribution of sex chromosome and cellular sexual identity towards the sex-specific germline piRNA program. We found that the presence of the Y chromosome is sufficient to recapitulate some aspects of the male piRNA program in a female cellular environment. Meanwhile, sexual identity controls the sexually divergent piRNA production from X-linked and autosomal loci, revealing a crucial input from sex determination into piRNA biogenesis. Sexual identity regulates piRNA biogenesis through Sxl and this effect is mediated in part through chromatin proteins Phf7 and Kipferl. Together, our work delineated the genetic control of a sex-specific piRNA program, where sex chromosome and sexual identity collectively sculpt an essential molecular trait.

genetics↗

Bacterial Argonaute proteins aid cell division in the presence of topoisomerase inhibitors in Escherichia coli

Prokaryotic Argonaute (pAgo) proteins are guide-dependent nucleases that function in host defense against invaders. Recently, it was shown that TtAgo from Thermus thermophilus also participates in the completion of DNA replication by decatenating chromosomal DNA. Here, we show that two pAgos from cyanobacteria Synechococcus elongatus (SeAgo) and Limnothrix roseae (LrAgo) act as DNA-guided DNA nucleases in Escherichia coli and aid cell division in the presence of the gyrase inhibitor ciprofloxacin. Both pAgos are preferentially loaded with small DNA guides derived from the sites of replication termination. The amount of pAgo-associated small DNAs (smDNAs) from the termination sites is increased in the presence ciprofloxacin, suggesting that smDNA biogenesis depends on DNA replication and is stimulated by gyrase inhibition. Ciprofloxacin also enhances asymmetry in the distribution of smDNAs around Chi-sites, indicating that it induces double-strand breaks that serve as a source of smDNA during their processing by RecBCD. While active in E. coli, SeAgo does not protect its native host S. elongatus from ciprofloxacin. These results suggest that pAgo nucleases help to complete replication of chromosomal DNA by targeting the sites of termination, and may switch their functional activities when expressed in different host species.

molecular biology↗

Pervasive SUMOylation of heterochromatin and piRNA pathway proteins

Genome regulation involves complex and highly regulated protein interactions that are often mediated through post-translational modifications (PTMs). SUMOylation - the covalent attachment of the small ubiquitin-like modifier (SUMO) - is a conserved PTM in eukaryotes that has been implicated in a number of essential processes such as nuclear import, DNA damage repair, transcriptional control, and chromatin organization. In Drosophila, SUMO is essential for viability and its depletion from the female germline causes infertility associated with global loss of heterochromatin, and illicit upregulation of transposons and lineage-inappropriate genes. However, the specific targets of SUMO and its mechanistic role in different cellular pathways are still poorly understood. Here, we developed a proteomics-based strategy to characterize the SUMOylated proteome in Drosophila that allowed us to identify ~1500 SUMO sites in 843 proteins in the fly ovary. A high-confidence set of SUMOylated proteins is highly enriched in factors involved in heterochromatin regulation and several different aspects of the piRNA pathway that represses transposons, including piRNA biogenesis and function. Furthermore, we show that SUMOylation of several piRNA pathway proteins occurs in a Piwi-dependent manner, indicating a functional implication of this modification in the cellular response to transposon activity. Together, these data highlight the impact of SUMOylation on epigenetic regulation and reveal an unexpectedly broad role of the SUMO pathway in the cellular defense against genomic parasites. Finally, this work provides a valuable resource and a system that can be adapted to the study of SUMOylation in other Drosophila tissues.

molecular biology↗

Specific targeting of plasmids with Argonaute enables genome editing

Prokaryotic Argonautes (pAgos) are programmable nucleases involved in cell defense against invading DNA. Recent studies showed that pAgos can bind small single-stranded guide DNAs (gDNAs) to recognize and cleave complementary DNA in vitro. In vivo pAgos preferentially target plasmids, phages and multicopy genetic elements. Here, we reveal that CbAgo nuclease from Clostridium butyricum can be used for genomic DNA cleavage and engineering in bacteria. CbAgo-dependent targeting of genomic loci with plasmid-derived gDNAs promotes recombination between plasmid and chromosomal DNA. Efficient genome cleavage and recombineering depends on the catalytic activity of CbAgo, its interactions with gDNAs, and the extent of homology between plasmid and chromosomal sequences. Specific targeting of plasmids with Argonautes can be used to integrate plasmid-encoded sequences into the chromosome thus enabling genome editing. One-Sentence SummaryProkaryotic Argonaute nuclease induces DNA interference between plasmid and chromosomal DNA to promote genome recombineering.

molecular biology↗

piRNA-mediated gene regulation and adaptation to sex-specific transposon expression in D. melanogaster male germline

Small non-coding piRNAs act as sequence-specific guides to repress complementary targets in Metazoa. Prior studies in Drosophila ovaries have demonstrated the function of piRNA pathway in transposon silencing and therefore genome defense. However, the ability of piRNA program to respond to different transposon landscape and the role of piRNAs in regulating host gene expression remain poorly understood. Here, we comprehensively analyzed piRNA expression and defined the repertoire of their targets in Drosophila melanogaster testes. Comparison of piRNA programs between sexes revealed sexual dimorphism in piRNA programs that parallel sex-specific transposon expression. Using a novel bioinformatic pipeline, we identified new piRNA clusters and established complex satellites as dual-strand piRNA clusters. While sharing most piRNA clusters, two sexes employ them differentially to combat sex-specific transposon landscape. We found several host genes targeted by piRNAs in testis, including CG12717/pita, a SUMO protease gene. piRNAs encoded on Y chromosome silence pita, but not its paralog, to exert sex- and paralog-specific gene regulation. Interestingly, pita is targeted by endogenous siRNAs in a sibling species, Drosophila mauritiana, suggesting distinct but related silencing strategies invented in recent evolution to regulate a conserved protein-encoding gene.

molecular biology↗

RDC complex executes a dynamic piRNA program during Drosophila spermatogenesis to safeguard male fertility

piRNAs are small non-coding RNAs that guide the silencing of transposons and other targets in animal gonads. In Drosophila female germline, many piRNA source loci dubbed piRNA clusters lack hallmarks of active genes and exploit an alternative path for transcription, which relies on the Rhino-Deadlock-Cutoff (RDC) complex. It remains to date unknown how piRNA cluster transcription is regulated in the male germline. We found that components of RDC complex are expressed in male germ cells during early spermatogenesis, from germline stem cells (GSCs) to early spermatocytes. RDC is essential for expression of dual-strand piRNA clusters and transposon silencing in testis; however, it is dispensable for expression of Y-linked Suppressor of Stellate piRNAs and therefore Stellate silencing. Despite intact Stellate repression, rhi mutant males exhibited compromised fertility accompanied by germline DNA damage and GSC loss. Thus, piRNA-guided repression is essential for normal spermatogenesis beyond Stellate silencing. While RDC associates with multiple piRNA clusters in GSCs and early spermatogonia, its localization changes in later stages as RDC concentrates on a single X-linked locus, AT-chX. Dynamic RDC localization is paralleled by changes in piRNA cluster expression, indicating that RDC executes a fluid piRNA program during different stages of spermatogenesis.

molecular biology↗

pAgo-induced DNA interference protects bacteria from invader DNA

Members of the conserved Argonaute protein family use small RNA guides to find their mRNA targets to regulate gene expression and suppress mobile genetic elements in eukaryotes. Argonautes are also present in many bacterial and archaeal species 1-3. Unlike eukaryotic proteins, several studied prokaryotic Argonautes use small DNA guides to cleave DNA, a process dubbed DNA interference 4-8. However, the natural functions and targets of DNA interference are poorly understood and the mechanisms of DNA guide generation and target discrimination remain unknown. Here, we studied the in vivo activities of a bacterial Argonaute nuclease CbAgo and demonstrated that it induces cleavage of multicopy genetic elements, including plasmids, transposons and repetitive chromosomal loci. Generation of small DNA guides employed by CbAgo requires cooperation between its intrinsic endonuclease activity and the cellular double-strand break repair machinery. The mechanism of guide generation ensures that small DNA guides are enriched in sequences that target foreign DNA and endows CbAgo with capacity to eliminate plasmids and fight phage infection. Similar principles may underlie the specificity of self-nonself discrimination by diverse defense systems in prokaryotes.

molecular biology↗

The SUMO ligase Su(var)2-10 links piRNA-guided target recognition to chromatin silencing

Regulation of transcription is the main mechanism responsible for precise control of gene expression. While the majority of transcriptional regulation is mediated by a multitude of DNA-binding transcription factors that bind to regulatory gene regions, an elegant alternative strategy employs small RNA guides, piwi-interacting RNAs (piRNAs) to identify targets of transcriptional repression. Here we show that in Drosophila the small ubiquitin-like protein SUMO and the SUMO E3 ligase Su(var)2-10 are required for piRNA-guided deposition of repressive chromatin marks and transcriptional silencing of piRNA targets. Su(var)2-10 links the piRNA-guided target recognition complex to the silencing effector by binding the piRNA/Piwi complex and inducing SUMO-dependent recruitment of the SetDB1/Wde histone methyltransferase effector. We propose that in Drosophila, the nuclear piRNA pathway has co-opted a conserved mechanism of SUMO-dependent recruitment of the SetDB1/Wde chromatin modifier to confer repression of genomic parasites. Highlights- piRNA-induced transposon silencing requires SUMO and the SUMO E3 ligase Su(var)2-10 - Su(var)2-10 links the target recognition complex to the silencing effector - Su(var)2-10 binds the piRNA-guided target recognition complex and deposits SUMO on target chromatin - Su(var)2-10 induces SUMO-dependent recruitment of the SetDB1/Wde histone methyltransferase to target loci

molecular biology↗

The SUMO ligase Su(var)2-10 controls eu- and heterochromatic gene expression via establishment of H3K9 trimethylation and negative feedback regulation

Chromatin is critical for genome compaction and gene expression. On a coarse scale, the genome is divided into euchromatin, which harbors the majority of genes and is enriched in active chromatin marks, and heterochromatin, which is gene-poor but repeat-rich. The conserved molecular hallmark of heterochromatin is the H3K9me3 modification, which is associated with gene silencing. We found that in Drosophila deposition of most of the H3K9me3 mark depends on SUMO and the SUMO-ligase Su(var)2-10, which recruits the histone methyltransferase complex SetDB1/Wde. In addition to repressing repeats, H3K9me3 also influences expression of both hetero- and euchromatic host genes. High H3K9me3 levels in heterochromatin are required to suppress spurious non-canonical transcription and ensure proper gene expression. In euchromatin, a set of conserved genes is repressed by Su(var)2-10/SetDB1-induced H3K9 trimethylation ensuring tissue-specific gene expression. Several components of heterochromatin are themselves repressed by this pathway providing a negative feedback mechanism to ensure chromatin homeostasis. Highlights- Proper expression of host genes residing in heterochromatin requires Su(var)2-10-dependent installation of the H3K9me3 mark to suppress spurious non-canonical transcription. - A set of euchromatic host genes is repressed by transposon-independent installation of H3K9me3 in a process that depends on Su(var)2-10 and SUMO. - Installation of H3K9me3 via Su(var)2-10 ensures tissue-specific gene expression. - H3K9me3-dependent silencing of genes encoding proteins involved in heterochromatin formation provides negative feedback regulation to maintain heterochromatin homeostasis.

molecular biology↗