TDRD5 binds piRNA precursors and selectively enhances pachytene piRNA processing in mice

Ding, Deqiang; Liu, Jiali; Midic, Uros; Wu, Yingjie; Dong, Kunzhe; Melnick, Ashley; Latham, Keith E.; Chen, Chen

doi:10.1038/s41467-017-02622-w

Cited by 49 publications

(67 citation statements)

References 48 publications

(66 reference statements)

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“…The closest Drosophila homolog to tdrd5p is tejas , and the closest mammalian homolog to tdrd5p is mouse TDRD5. Both tejas and TDRD5 have been shown to function in the piRNA pathway and to repress the expression of transposons in the germline [25,26,34]. Interestingly, we found no changes in transposon expression in tdrd5p mutants in our RNA-seq analysis (data not shown).…”

Section: Resultsmentioning

confidence: 53%

tudor-domain containing protein 5-primepromotes male sexual identity in theDrosophilagermline and is repressed in females bySex lethal

Primus

Pozmanter

Baxter

et al. 2018

Preprint

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For sexually reproducing organisms, production of male or female gametes depends on specifying the correct sexual identity in the germline. In D. melanogaster, Sex lethal (Sxl) is the key gene that controls sex determination in both the soma and the germline, but how it does so in the germline is unknown, other than that it is different than in the soma. We conducted an RNA expression profiling experiment to identify direct and indirect germline targets of Sxl specifically in the undifferentiated germline. We find that, in these cells, Sxl loss does not lead to a global masculinization observed at the whole-genome level. In contrast, Sxl appears to affect a discrete set of genes required in the male germline, such as Phf7. We also identify tudor domain containing protein 5-prime (tdrd5p) as a target for Sxl regulation that is important for male germline identity. tdrd5p is repressed by Sxl in female germ cells, but is highly expressed in male germ cells where it promotes proper male fertility and germline differentiation. Additionally, Tdrd5p localizes to cytoplasmic granules with some characteristics of RNA Processing (P-) Bodies, suggesting that it promotes male identity in the germline by regulating post-transcriptional gene expression.Author summaryLike humans, all sexually reproducing organisms require gametes to reproduce. Gametes are made by specialized cells called germ cells, which must have the correct sexual identity information to properly make sperm or eggs. In fruit flies, germ cell sexual identity is controlled by the RNA-binding protein Sxl, which is expressed only in females. To better understand how Sxl promotes female identity, we conducted an RNA expression profiling experiment to identify genes whose expression changes in response to the loss of Sxl from germ cells. Here, we identify tudor domain containing protein 5-prime (tdrd5p), which is expressed 17-fold higher in ovaries lacking Sxl compared to control ovaries. Additionally, tdrd5p plays an important role in males as male flies that are mutant for this gene cannot make sperm properly and thus are less fertile. Moreover, we find that tdrd5p promotes male identity in the germline, as several experiments show that it can shift the germ cell developmental program from female to male. This study tells us that Sxl promotes female identity in germ cells by repressing genes, like tdrd5p, that promote male identity. Future studies into the function of tdrd5p will provide mechanistic insight into how this gene promotes male identity.

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Section: Resultsmentioning

confidence: 53%

tudor-domain containing protein 5-primepromotes male sexual identity in theDrosophilagermline and is repressed in females bySex lethal

Primus

Pozmanter

Baxter

et al. 2018

Preprint

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“…The Chr18 piRNA cluster is ranked as the highest piRNA-producing locus among all (>200) pre-and pachytene piRNA clusters 28 . While Chr18 +/∆ control mice had normal fertility and no discernable phenotype, transcriptome analysis revealed minor changes of mRNA abundance between Chr18 +/∆ and Chr18 ∆/∆ testes which suggests compensatory mechanisms that could partially account for the difficulty in identifying pachytene piRNA targets and function 57,58 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, accurate post-transcriptional quality control of RNA and proteins is critical for normal spermatogenesis. To explore the functional importance of pachytene piRNAs, we have used CRISPR/Cas9 genome editing to establish mouse lines unable to express specific piRNA precursors from a highly prolific 28 , bi-directional pachytene piRNA clusters on Chromosome 18 (Chr18). By investigating proteome and transcriptome profiles of these non-proliferating cells, we have discovered that Chr18 pachytene piRNAs maintain protein homeostasis and ensure proper acrosome formation.…”

Section: Introductionmentioning

confidence: 99%

Sperm acrosome overgrowth and infertility in mice lacking chromosome 18 pachytene piRNA

Choi

Zheng-pin

Dean

2020

Preprint

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AbstractpiRNAs are germline-specific, small non-coding RNAs required to maintain genome integrity and preserve RNA homeostasis during male gametogenesis. In murine adult testes, the highest levels of piRNAs are present in the pachytene stage of meiosis, but their mode of action and function remains incompletely understood. We previously reported that BTBD18 binds to 50 pachytene piRNA-producing loci. Here we show that spermatozoa in gene-edited mice lacking a BTBD18 targeted pachytene piRNA cluster on Chr18 have severe sperm head dysmorphology, poor motility, impaired acrosome exocytosis and are sterile. The absence of Chr18 piRNA results in an imbalance of heat shock proteins associated with renaturing proteins and the ubiquitin-proteasome system involved with protein degradation. The mutant phenotype arises from aberrant formation of proacrosomal vesicles, distortion of the trans-Golgi network, and up-regulation of GOLGA2 associated with acrosome dysgenesis. Collectively, our findings reveal central role of pachytene piRNAs in controlling spermiogenesis and male fertility.

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“…TDRD5-CLIP and MILI-CLIP sequencing data (SRA accession number: SRP093845) ( 30 ) were used to analyze for nucleotide composition and G-quadruplex prediction. Sequenced TDRD5-CLIP and MILI-CLIP reads were processed with fastx_clipper to clip the sequencing adapter read-through.…”

Section: Methodsmentioning

confidence: 99%

“…Sequenced TDRD5-CLIP and MILI-CLIP reads were processed with fastx_clipper to clip the sequencing adapter read-through. Clipped reads were filtered by length (≥15nt) and aligned to the following sets of sequences: 214 piRNA clusters, coding RNAs, noncoding RNAs, repeats and intron ( 30 , 31 ). Alignments were performed using Bowtie (one base mismatch allowed).…”

Section: Methodsmentioning

confidence: 99%

LOTUS domain is a novel class of G-rich and G-quadruplex RNA binding domain

Ding

Wei

Dong

et al. 2020

Nucleic Acids Research

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LOTUS domains are helix-turn-helix protein folds identified in essential germline proteins and are conserved in prokaryotes and eukaryotes. Despite originally predicted as an RNA binding domain, its molecular binding activity towards RNA and protein is controversial. In particular, the most conserved binding property for the LOTUS domain family remains unknown. Here, we uncovered an unexpected specific interaction of LOTUS domains with G-rich RNA sequences. Intriguingly, LOTUS domains exhibit high affinity to RNA G-quadruplex tertiary structures implicated in diverse cellular processes including piRNA biogenesis. This novel LOTUS domain-RNA interaction is conserved in bacteria, plants and animals, comprising the most ancient binding feature of the LOTUS domain family. By contrast, LOTUS domains do not preferentially interact with DNA G-quadruplexes. We further show that a subset of LOTUS domains display both RNA and protein binding activities. These findings identify the LOTUS domain as a specialized RNA binding domain across phyla and underscore the molecular mechanism underlying the function of LOTUS domain-containing proteins in RNA metabolism and regulation.

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TDRD5 binds piRNA precursors and selectively enhances pachytene piRNA processing in mice

Cited by 49 publications

References 48 publications

tudor-domain containing protein 5-primepromotes male sexual identity in theDrosophilagermline and is repressed in females bySex lethal

tudor-domain containing protein 5-primepromotes male sexual identity in theDrosophilagermline and is repressed in females bySex lethal

Sperm acrosome overgrowth and infertility in mice lacking chromosome 18 pachytene piRNA

LOTUS domain is a novel class of G-rich and G-quadruplex RNA binding domain

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