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Tudor domain containing 12 (TDRD12) is essential for secondary piRNA biogenesis in mice

ABSTRACT: Piwi-interacting RNAs (piRNAs) are gonad-specific small RNAs that provide defence against transposable genetic elements called transposons. Our knowledge of piRNA biogenesis is sketchy, partly due to an incomplete inventory of the factors involved. Here, we identify Tudor domain-containing 12 (TDRD12; also known as ECAT8) as a novel piRNA biogenesis factor in mice. TDRD12 is detected in complexes containing MILI (PIWIL2), its associated primary piRNAs, and TDRD1, all of which are already implicated in secondary piRNA biogenesis. Male mice carrying either a nonsense point mutation (repro23 mice) or a targeted deletion in the Tdrd12 locus are infertile, and de-repress retrotransposons. We find that TDRD12 is dispensable for primary piRNA biogenesis but essential for production of secondary piRNAs that enter MIWI2 (PIWIL4). Cell culture studies with the insect orthologue of TDRD12 suggest a role for the multi-domain protein in mediating complex formation with other participants during secondary piRNA biogenesis.

ORGANISM(S): Mus musculus Bombyx mori

PROVIDER: GSE50544 | GEO | 2013/11/04

SECONDARY ACCESSION(S): PRJNA217917

REPOSITORIES: GEO

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Tudor domain containing 12 (TDRD12) is essential for secondary piRNA biogenesis in mice

Project description:Piwi-interacting RNAs (piRNAs) are gonad-specific small RNAs that provide defence against transposable genetic elements called transposons. Our knowledge of piRNA biogenesis is sketchy, partly due to an incomplete inventory of the factors involved. Here, we identify Tudor domain-containing 12 (TDRD12; also known as ECAT8) as a novel piRNA biogenesis factor in mice. TDRD12 is detected in complexes containing MILI (PIWIL2), its associated primary piRNAs, and TDRD1, all of which are already implicated in secondary piRNA biogenesis. Male mice carrying either a nonsense point mutation (repro23 mice) or a targeted deletion in the Tdrd12 locus are infertile, and de-repress retrotransposons. We find that TDRD12 is dispensable for primary piRNA biogenesis but essential for production of secondary piRNAs that enter MIWI2 (PIWIL4). Cell culture studies with the insect orthologue of TDRD12 suggest a role for the multi-domain protein in mediating complex formation with other participants during secondary piRNA biogenesis. Total small RNA and immunoprecipitated small RNA were purified from mouse testis extract and Bmn4 cells for preparation of high-throughput sequencing libraries.

2013-11-04 | E-GEOD-50544 | biostudies-arrayexpress

Profiling of Mili and Miwi2 associated piRNAs in WT, MiliDAH, Miwi2DAH and Miwi2KO from E16.5 gonadocytes.

Project description:Piwi proteins and piRNAs have conserved functions in transposonM- silencing. The murine Piwi proteins Mili and Miwi2 direct epigeneticM- LINE1 (L1) and intracisternal A particle (IAP) transposon silencingM- during genome reprogramming in the embryonic male germline. PiwiM- proteins are proposed to be piRNA-guided endonucleases that initiateM- secondary piRNA biogenesis . However the actual contribution of theirM- endonuclease activities to piRNA biogenesis and transposon silencingM- remain unknown. To investigate the role of Piwi-catalyzedM- endonucleolytic activity, we engineered point mutations in the mouseM- that substitute the second D to an A in the catalytic triad (DDH) ofM- Mili and Miwi2, generating the MiliDAH and Miwi2DAH alleles,M- M- respectively. Analysis of Mili-bound piRNAs from homozygous MiliDAHM- fetal gonadocytes revealed the failure of transposon piRNA amplification resulting in the stark reduction of piRNA bound withinM- Miwi2 ribonuclear particles (RNPs). We find that Mili-mediated piRNA amplification is selectively required for L1 but not IAP silencing.M- The defective piRNA pathway in MiliDAH mice results in spermatogenic failure and sterility. Surprisingly, homozygous Miwi2DAH mice areM- fertile, transposon silencing is established normally and no defectsM- in secondary piRNA biogenesis are observed. In addition, the hallmarks of piRNA amplification are observed in Miwi2-deficient gonadocytes. WeM- conclude that cycles of intra-Mili secondary piRNA biogenesis fuelM- piRNA amplification that is selectively required for L1 silencing.M-

2011-10-28 | E-MTAB-730 | biostudies-arrayexpress

Exonuclease domain-containing 1 enhances MIWI2 piRNA biogenesis via its interaction with TDRD12

Project description:PIWI proteins and their associated small RNAs called PIWI-interacting RNAs (piRNAs) restrict transposon activity in animal gonads to ensure fertility. Distinct biogenesis pathways load piRNAs into the PIWI proteins MILI and MIWI2 in the mouse male embryonic germline. While most of MILI piRNAs derive via a slicer-independent pathway, a MILI slicer endonuclease-initiated pathway loads nuclear MIWI2 with a series of phased piRNAs. Tudor domain-containing 12 (TDRD12) and its interaction partner Exonuclease domain-containing 1 (EXD1) are required for loading MIWI2, but only Tdrd12 is essential for fertility, leaving us with no explanation for the physiological role of Exd1. Using an artificial piRNA precursor, we demonstrate that MILI-triggered piRNA biogenesis is greatly reduced in the Exd1 mutant. The situation deteriorates in the sensitized Exd1 mutant (Exd1-/-; Tdrd12+/-), where diminished MIWI2 piRNA levels de-repress LINE1 retrotransposons, causing infertility. Thus, EXD1 enhances slicing-triggered MIWI2 piRNA biogenesis via a functional interaction with TDRD12.

2018-09-27 | GSE119447 | GEO

Loss of the Mili-interacting Tdrd1 activates transposons and alters Mili-associated small RNA profile

Project description:Piwi proteins and their associated Piwi-interacting RNAs (piRNAs) are implicated in transposon silencing in the murine germline. There is currently little information on additional proteins in the murine Piwi complex and how they might regulate the entry of transcripts that accumulate as piRNAs in the Piwi ribonucleoprotein (piRNP). We isolated Mili-containing complexes from adult mouse testes and identified Tudor domain-containing protein 1 (Tdrd1) as a factor specifically associated with the Mili piRNP throughout spermatogenesis. Complex formation is promoted by the recognition of symmetrically dimethylated arginines at the N-terminus of Mili by the Tudor domains of Tdrd1. Similar to a Mili mutant, mice lacking Tdrd1 show derepression of L1 transposons accompanied by a loss of DNA methylation of their regulatory elements, and delocalization of Miwi2 from the nucleus to the cytoplasm. Finally, we show that Mili piRNPs devoid of Tdrd1 accept the entry of abundant cellular transcripts into the piRNA pathway and accumulate piRNAs with a profile that is drastically different from the wild-type. Our data suggests that Mili recruits Tdrd1 to ensure only the entry of transcripts that contribute to its normal piRNA pool.

2009-05-24 | GSE16023 | GEO

Loss of the Mili-interacting Tdrd1 activates transposons and alters Mili-associated small RNA profile

2009-05-24 | E-GEOD-16023 | biostudies-arrayexpress

Epigenetic control of transposable elements in the mouse male germ line by Tex15

Project description:The piRNA biogenesis was evaluated in the mouse testes lacking TEX15. Total small RNAs, MILI-, and MIWI2-associated small RNAs from control (Tex15+/-) and Tex15(-/-) knock-out testes were sequenced. Data analysis revealed that the abundance of miRNAs and piRNAs was comparable between control and Tex15 knock-out testes, suggesting that loss of TEX15 function does not impair piRNA biogenesis. However, the relative abundance of MILI- and MIWI2-bound sense piRNAs derived from transposable elements was increased.

2020-11-27 | GSE107832 | GEO

A MILI-independent piRNA biogenesis pathway empowers partial germline reprogramming.

Project description:In mice, the PIWI-piRNA pathway is essential to re-establish transposon silencing during male germline reprogramming. The cytoplasmic PIWI protein MILI mediates piRNA-guided transposon RNA cleavage as well as piRNA amplification. MIWI2-bound piRNAs and its nuclear localization are proposed to be dependent upon MILI function. Here, we demonstrate the existence of a piRNA biogenesis pathway that in the absence of MILI that sustains partial MIWI2 function and reprogramming activity.

2017-04-25 | E-MTAB-5561 | biostudies-arrayexpress

A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice

Project description:We examined the construction of the piRNA system in the restricted developmental window in which methylation patterns are set during mammalian embryogenesis. We find robust expression of two Piwi family proteins, MIWI2 and MILI. Their associated piRNA profiles reveal differences from Drosophila wherein large piRNA clusters act as master regulators of silencing. Instead, in mammals, dispersed transposon copies initiate the pathway, producing primary piRNAs, which predominantly join MILI in the cytoplasm. MIWI2, whose nuclear localization and association with piRNAs depend upon MILI, is enriched for secondary piRNAs antisense to the elements that it controls. The Piwi pathway lies upstream of known mediators of DNA methylation, since piRNAs are still produced in Dnmt3L mutants, which fail to methylate transposons. This implicates piRNAs as specificity determinants of DNA methylation in germ cells. Examination of total small RNA and MILI associated piRNAs in embryonic and post-birth mouse testes, MIWI2-associated piRNAs in embryonic testes.

2008-10-01 | E-GEOD-12757 | biostudies-arrayexpress

A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice

2008-10-01 | GSE12757 | GEO

PIWI slicing and EXD1 drive biogenesis of nuclear piRNAs from cytosolic targets of the mouse piRNA pathway

Project description:PIWI-interacting RNAs (piRNAs) guide PIWI proteins to suppress transposable elements in animal gonads. Here we demonstrate that in the mouse embryonic male germline, endonucleolytic cleavage (slicing) of a transcript by cytosolic MILI acts as a trigger to initiate its further 5??3? processing into non-overlapping fragments. These fragments accumulate as new piRNAs within the nuclear PIWI protein MIWI2. We identify Exonuclease domain-containing 1 (EXD1) as a partner of the established MIWI2 piRNA biogenesis factor TDRD12. Although EXD1 homodimers are inactive as a nuclease, it functions as an RNA adapter within a PET (PIWI-EXD1-Tdrd12) complex. Loss of Exd1 impacts biogenesis of MIWI2 piRNAs and displays a reduction in sequences generated by MILI slicing. This results in selective depletion of repeat piRNAs that target active retrotransposons like LINE1, which are de-repressed in the mutant. We propose that PIWI slicing and EXD1 promote coordination of nucleo-cytoplasmic silencing via piRNA biogenesis. Immunoprecipitated or total small RNAs were purified and sequenced from P0 mouse testis of Exd1+/- and Exd1 -/- mice. Testes of three males were pooled together and MILI and MIWI2 immunoprecipitation was performed or total small RNAs were purified. Two replicas from different pools were prepared. For Rosa26-pi reporter mouse P0 testes of three males were pooled together and MILI and MIWI2 immunoprecipitation was performed.

2015-12-04 | E-GEOD-74423 | biostudies-arrayexpress

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