Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354317 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5031520.fastq.gz | Fastqsanger.gz | |||
| SRR5031517.fastq.gz | Fastqsanger.gz | |||
| SRR5031518.fastq.gz | Fastqsanger.gz | |||
| SRR5031519.fastq.gz | Fastqsanger.gz |
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Project description:The de novo DNA methyltransferase DNMT3C protects male fertility from transposon activity
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Project description:In the male mouse germline, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germline remains unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of one of these pathogenic alleles, we discovered that the uncharacterised protein C19ORF84 interacts with SPOCD1. DNMT3C, the DNA methyltransferase responsible for transposon methylation, associates with SPOCD1 and C19ORF84 in foetal gonocytes. Furthermore, C19ORF84 is essential for piRNA-directed DNA methylation and male mouse fertility. Finally, C19ORF84 mediates the in vivo association of SPOCD1 with the de novo methylation machinery. In summary, we have discovered a conserved role for the human piRNA pathway in transposon silencing and C19ORF84, an uncharacterised protein essential for orchestrating piRNA-directed DNA methylation.
2024-02-14 | PXD047331 | Pride
Project description:Transcriptional silencing by heritable cytosine-5 methylation is an ancient strategy to repress transposable elements. It was previously thought that mammals possess four DNA methyltransferase paralogs—Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l—that establish and maintain cytosine-5 methylation. Here we identify a fifth paralog, Dnmt3c, that is essential for retrotransposon methylation and repression in the mouse male germline. From a phenotype-based forward genetics screen, we isolated a mutant mouse called ‘rahu’, which displays severe defects in double-strand-break repair and homologous chromosome synapsis during male meiosis, resulting in sterility. rahu is an allele of a transcription unit (Gm14490, renamed Dnmt3c) that was previously mis-annotated as a Dnmt3-family pseudogene. Dnmt3c encodes a cytosine methyltransferase homolog, and Dnmt3crahu mutants harbor a non-synonymous mutation of a conserved residue within one of its cytosine methyltransferase motifs, similar to a mutation in human DNMT3B observed in patients with immunodeficiency, centromeric instability and facial anomalies syndrome. The rahu mutation lies at a potential dimerization interface and near the potential DNA binding interface, suggesting that it compromises protein-protein and/or protein-DNA interactions required for normal DNMT3C function in vivo. Dnmt3crahu mutant males fail to establish normal methylation within LINE and LTR retrotransposon sequences in the germline and accumulate higher levels of transposon-derived transcripts and proteins, particularly from distinct L1 and ERVK retrotransposon families. Phylogenetic analysis indicates that Dnmt3c arose during rodent evolution by tandem duplication of Dnmt3b, after the divergence of the Dipodoidea and Muroidea superfamilies. These findings provide insight into the evolutionary dynamics and functional specialization of the transposon suppression machinery critical for mammalian sexual reproduction and epigenetic regulation.
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2025-05-09 | GSE296286 | GEO
Project description:The Microrchidia (Morc) family of GHKL ATPases are present in a wide variety of prokaryotic and eukaryotic organisms but are of largely unknown function. Genetic screens in Arabidopsis thaliana have identified Morc genes as important repressors of transposons and other DNA methylated and silent genes. MORC1 deficient mice were previously found to display male-specific germ cell loss and infertility. Here we show that MORC1 is responsible for transposon repression in the male germline in a pattern that is similar to that observed for germ cells deficient for the DNA methyltransferase homolog DNMT3L. Morc1 mutants show highly localized defects in the establishment of DNA methylation at specific classes of transposons, and this is associated with failed transposon silencing at these sites. Our results identify MORC1 as an important new regulator of the epigenetic landscape of male germ cells during the period of global de novo methylation. This data includes: 47 RNA-seq, 4 smRNA-seq, 6 BS-seq, and 2 ChIP-seq datasets
2014-12-12 | E-GEOD-63048 | biostudies-arrayexpress
Project description:The Microrchidia (Morc) family of GHKL ATPases are present in a wide variety of prokaryotic and eukaryotic organisms but are of largely unknown function. Genetic screens in Arabidopsis thaliana have identified Morc genes as important repressors of transposons and other DNA methylated and silent genes. MORC1 deficient mice were previously found to display male-specific germ cell loss and infertility. Here we show that MORC1 is responsible for transposon repression in the male germline in a pattern that is similar to that observed for germ cells deficient for the DNA methyltransferase homolog DNMT3L. Morc1 mutants show highly localized defects in the establishment of DNA methylation at specific classes of transposons, and this is associated with failed transposon silencing at these sites. Our results identify MORC1 as an important new regulator of the epigenetic landscape of male germ cells during the period of global de novo methylation.
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Project description:The mouse PIWI-interacting RNA (piRNA) pathway provides anti-transposon immunity to the developing male germline by directing transposon DNA methylation. The first step in this process is the recruitment of SPOCD1 to young LINE1 loci 1 followed in the second step by piRNA-mediated tethering of the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript. To protect the germline, the piRNA pathway needs to methylate all active transposon copies but how this is achieved remains unknown. Here, we show that nuclear piRNA and de novo methylation factors are all euchromatic. We find that SPOCD1 directly interacts with the nuclear pore component TPR, which forms heterochromatin exclusion zones adjacent to nuclear pores. In foetal gonocytes undergoing piRNA-directed DNA methylation, TPR is found both at the nuclear periphery but also abundantly throughout the nucleoplasm. We found that the SPOCD1-TPR interaction is required for complete non-stochastic piRNA-directed LINE1 methylation. The loss of the SPOCD1-TPR interaction results in a fraction of SPOCD1 and other chromatin-bound piRNA factors to relocalise to constitutive heterochromatin where they are no longer accessible to MIWI2 and the de novo methylation machinery. We propose that TPR-mediated heterochromatin exclusion provides a nowhere-to-hide mechanism for SPOCD1-bound LINE1 loci throughout the nucleoplasm. In summary, the piRNA pathway has co-opted TPR to guarantee LINE1s are euchromatic and accessible to the piRNA and de novo methylation machineries.
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