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A Pandas complex adapted for piRNA-guided transposon silencing (CLIP-seq)

ABSTRACT: The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila ovaries, Panoramix (Panx) enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occur remain elusive. Here, we show that Panx functions together with a germline specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15) as a ternary complex to suppress transposon expression. Structural and functional analysis demonstrate that dNxf2 binds Panx via its UBA domain and play an important role in transposon silencing through binding to transposon transcripts directly. Unexpectedly, dNxf2 interacts directly with dNxf1 (TAP), which is also essential for transposon silencing. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. Therefore, we propose that dNxf2 may function as a Pandas (Panoramix dNxf2 dependent TAP/p15 silencing) complex, which counteracts the canonical RNA exporting machinery (TAP/p15) and restricts transposons to nuclear peripheries. Our finding may have broader implications for understanding how RNA metabolism modulates epigenetic gene silencing and heterochromatin formation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE130041 | GEO | 2019/08/09

REPOSITORIES: GEO

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A Pandas complex adapted for piRNA-guided transposon silencing (RNA-seq)

Project description:The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila ovaries, Panoramix (Panx) enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occur remain elusive. Here, we show that Panx functions together with a germline specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15) as a ternary complex to suppress transposon expression. Structural and functional analysis demonstrate that dNxf2 binds Panx via its UBA domain and play an important role in transposon silencing through binding to transposon transcripts directly. Unexpectedly, dNxf2 interacts directly with dNxf1 (TAP), which is also essential for transposon silencing. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. Therefore, we propose that dNxf2 may function as a Pandas (Panoramix dNxf2 dependent TAP/p15 silencing) complex, which counteracts the canonical RNA exporting machinery (TAP/p15) and restricts transposons to nuclear peripheries. Our finding may have broader implications for understanding how RNA metabolism modulates epigenetic gene silencing and heterochromatin formation.

2019-08-09 | GSE121158 | GEO

A Pandas complex adapted for piRNA-guided transposon silencing and heterochromatin formation

2019-08-09 | GSE130042 | GEO

A Pandas complex adapted for piRNA-guided transposon silencing and heterochromatin formation, Panx-IP-MS

Project description:The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila ovaries, Panoramix (Panx) enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occurs remain elusive. Here, we show that Panx functions together with a germline specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15), as a ternary complex to suppress transposon expression. Similar to Panx, dNxf2 is essential for animal fertility. Structural and functional analyses demonstrate that dNxf2 binds Panx via its UBA domain, which plays an important role in transposon silencing. Unexpectedly, dNxf2 interacts directly with dNxf1 (TAP), a general nuclear export factor. As a result, dNxf2 prevents dNxf1 from binding to the FG repeats of the nuclear pore complex, a process required for proper RNA export. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. Thus, dNxf2 functions in a Pandas (Panoramix dNxf2 dependent TAP/p15 silencing) complex, which counteracts the canonical RNA exporting machinery and restricts transposons to the nuclear peripheries. Our findings may have broader implications for understanding how RNA metabolism regulates epigenetic gene silencing and heterochromatin formation.

2019-08-06 | PXD014926 | iProX

piRNA-guided co-transcriptional silencing coopts nuclear export factors

Project description:The PIWI-interacting RNA (piRNA) pathway is a small RNA-based immune system that controls the expression of transposons and maintains genome integrity in animal germlines1,2. In Drosophila, piRNA-guided silencing is achieved, in part, via co-transcriptional repression of transposons by Piwi. This depends on Panoramix (Panx)3,4; however, precisely how an RNA binding event silences transcription remains to be determined. Here we show that Nuclear Export Factor 2 (Nxf2) and its co-factor, Nxt1, form a complex with Panx, and are required for co-transcriptional silencing of transposons in somatic and germline cells of the ovary. Tethering of Nxf2 to either RNA or DNA results in silencing of target loci and the concomitant accumulation of repressive chromatin marks. Nxf2 and Panx proteins are mutually required for proper localization and stability. We mapped the protein domains crucial for the Nxf2/Panx complex formation and show that the amino-terminal portion of Panx is sufficient to induce transcriptional silencing. Loss of Nxf2 or Panx results in nuclear accumulation of transposon transcripts, which is for some transposons Piwi-dependent.

2019-06-20 | PXD011415 | Pride

piRNA-guided co-transcriptional silencing coopts nuclear export factors

2019-06-20 | GSE121661 | GEO

A nuclear RNA export factor variant licenses piRNA-guided heterochromatin formation

Project description:Small RNA silencing pathways protect genome integrity in part through establishing heterochromatin at transposon loci. In animals, this process requires piRNA-guided targeting of nuclear PIWI proteins to nascent transcripts. The molecular events contributing to heterochromatin formation upon PIWI binding to nascent RNA, a transient molecule at chromatin, are unknown. Here, we identify SFINX, a protein complex that is required for Piwi-mediated co-transcriptional silencing in Drosophila. It consists of Nxf2—a variant of the nuclear RNA export factor Nxf1/Tap, the mRNA export co-factor Nxt1/p15, and the Piwi-associated protein Panoramix. In the absence of Nxf2, Panoramix is targeted for degradation and piRNA-loaded Piwi is unable to establish heterochromatin. Consequently, nxf2 mutants exhibit severe transposon de-repression and are sterile. We show that within SFINX, Panoramix connects to the heterochromatin machinery while Nxf2 enables target silencing via nascent RNA. Thus, the Nxf2-Nxt1 heterodimer—despite having originated from core mRNA export machinery—has been repurposed for heterochromatin formation. Our data establish an unexpected link between nuclear small RNA biology and NXF-variants, which are widespread in animal lineages, but mostly lack ascribed functions.

2019-06-12 | PXD011201 | Pride

Nuclear RNA export factor variant initiates piRNA-guided co-transcriptional silencing

Project description:PIWI-interacting RNAs (piRNAs) are germline-specific small RNAs that form effector complexes with PIWI proteins (Piwi–piRISC complexes) to preserve genomic integrity by repressing transposable elements (TEs). Among PIWI-clade proteins in Drosophila, Piwi transcriptionally silences its targets via heterochromatin formation characterised by H3K9me3 marks and the linker histone H1. Recent studies have shown that Panoramix (Panx) interacts with Piwi–piRISC complexes to induce transcriptional repression of targets mediated by the recruitment of H3K9me3 marks. Here, we identified Nxf2, a nuclear RNA export factor (NXF) variant, as a protein that forms a complex with Panx and Piwi. Nxf2 further associates with p15 (Nxt1), a co-adaptor for nuclear RNA export. However, unlike Nxf1 that plays a major role in mRNA export, Nxf2–p15 instead transcriptionally regulates TEs in the Piwi–piRNA pathway. Panx–Nxf2–p15 complex formation is necessary in the silencing by stabilizing protein levels of Nxf2 and Panx. Notably, ectopic targeting of Nxf2 initiates co-transcriptional repression of the target reporter in a manner independent of H3K9me3 marks or H1. However, continuous silencing requires HP1a and H1. The amino-terminal domain of Nxf2 harbouring RNA binding activity is essential for recruitment of the Piwi–piRISC complex to target TEs. Indeed, Nxf2 directly interacts with target TE transcripts in a Piwi-dependent manner. These findings suggest a model in which the Nxf2–Panx–p15 complex enforces the association of Piwi with target transcripts to trigger co-transcriptional repression, prior to heterochromatin formation in the nuclear piRNA pathway. Our results provide an unexpected connection between an NXF variant and small RNA-mediated co-transcriptional silencing.

2019-07-09 | GSE131950 | GEO

The nascent RNA binding complex SFiNX licenses piRNA-guided heterochromatin formation

Project description:The PIWI-interacting RNA (piRNA) pathway protects animal genome integrity in part through establishing repressive heterochromatin at transposon loci. Silencing requires piRNA- guided targeting of nuclear PIWI proteins to nascent transposon transcripts, yet the subsequent molecular events are not understood. Here, we identify SFiNX (Silencing Factor interacting Nuclear eXport variant), an interdependent protein complex required for Piwi-mediated co-transcriptional silencing in Drosophila. SFiNX consists of Nxf2-Nxt1, a gonad- specific variant of the heterodimeric mRNA export receptor Nxf1-Nxt1, and the Piwi-associated protein Panoramix. SFiNX mutant flies are sterile and exhibit transposon de-repression because piRNA-loaded Piwi is unable to establish heterochromatin. Within SFiNX, Panoramix recruits the cellular heterochromatin machinery, while Nxf2 binds the nascent target RNA and licenses co-transcriptional silencing. Our results reveal an unexpected, RNA-export independent role for Nxf2 in nuclear small RNA biology and suggest that NXF-variants, which have largely unknown function in animals, are functionally linked to the genome-transposon conflict.

2019-04-17 | GSE120617 | GEO

Dimerisation of the PICTS complex via LC8/Cut-up drives co-transcriptional transposon silencing in Drosophila

Project description:In animal gonads, the PIWI-interacting RNA (piRNA) pathway guards genome integrity in part through the co-transcriptional gene silencing of transposon insertions. In Drosophila ovaries, piRNA-loaded Piwi detects nascent transposon transcripts and instructs heterochromatin formation through the Panoramix-induced co-transcriptional silencing (PICTS) complex, containing Panoramix, Nxf2 and Nxt1. Here, we report that the highly conserved dynein light chain LC8/Cut-up (Ctp) is an essential component of the PICTS complex. Loss of Ctp results in transposon de-repression and a reduction in repressive chromatin marks specifically at transposon loci. In turn, Ctp can enforce transcriptional silencing when artificially recruited to RNA and DNA reporters. We show that Ctp drives dimerisation of the PICTS complex through its interaction with conserved motifs within Panoramix. Artificial dimerisation of Panoramix bypasses the necessity for its interaction with Ctp, demonstrating that conscription of a protein from a ubiquitous cellular machinery has fulfilled a fundamental requirement for a transposon silencing complex.

2021-01-26 | PXD022105 | Pride

Dimerisation of the PICTS complex via LC8/Cut-up drives co-transcriptional transposon silencing in Drosophila

2021-01-26 | PXD022103 | Pride

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