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PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos

ABSTRACT: Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which entails comprehensive erasure of DNA methylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs caused complete male and female sterility, which is preceded by upregulation of LINE1 and IAP transposons and DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation and early embryonic lethality. We detected the PRMT5-catalysed repressive H2A/H4R3me2s modification on LINE1 and IAP in early wildtype PGCs, directly implicating this mark in the maintenance of transposon silencing during DNA hypomethylation. PRMT5 subsequently translocates back to the cytoplasm of PGCs to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA re-methylation. Thus, PRMT5 has a novel direct role in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation PGCs mRNA profiles of embryonic day 11.5 dpc control (Blimp1Cre;Prmt5flox/+) and Prmt5 germ cell knockout (Blimp1Cre;Prmt5 flox/flox) were generated by deep sequencing (SOLiD next generation sequencing).

ORGANISM(S): Mus musculus

SUBMITTER: Azim Surani

PROVIDER: E-GEOD-61216 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos

Project description:Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which entails comprehensive erasure of DNA methylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs caused complete male and female sterility, which is preceded by upregulation of LINE1 and IAP transposons and DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation and early embryonic lethality. We detected the PRMT5-catalysed repressive H2A/H4R3me2s modification on LINE1 and IAP in early wildtype PGCs, directly implicating this mark in the maintenance of transposon silencing during DNA hypomethylation. PRMT5 subsequently translocates back to the cytoplasm of PGCs to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA re-methylation. Thus, PRMT5 has a novel direct role in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation PGCs mRNA profiles of embryonic day 11.5 dpc control (Blimp1Cre;Prmt5flox/+) and Prmt5 germ cell knockout (Blimp1Cre;Prmt5 flox/flox) were generated by deep sequencing (SOLiD next generation sequencing).

2014-11-14 | E-GEOD-60875 | biostudies-arrayexpress

PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos

2014-11-14 | GSE60875 | GEO

Setdb1 is required for persistence of H3K9me3 and repression of endogenous retroviruses in mouse primordial germ cells

Project description:Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at ~E15.5 in prospermatogonia. Earlier in germline development however, the genome, including most retrotransposons, is progressively demethylated, with young ERVK and ERV1 elements retaining intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low input ChIP-seq method. Although these repressive histone modifications are predominantly found on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated LTRs and LINE1 elements. Germline-specific conditional knock-out (KO) of the H3K9 methyltransferase SETDB1 yields a decrease of both histone marks and DNA methylation at H3K9me3 enriched retrotransposon families. Strikingly, Setdb1-KO E13.5 PGCs show concomitant de-repression of many marked ERVs, including IAP, ETn and ERVK10C elements and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline. H3K9me3, H3K27me3 and expression profiles in Setdb1 WT, Het and KO male and female E13.5 PGCs.

2014-09-01 | E-GEOD-60377 | 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

Setdb1 is required for persistence of H3K9me3 and repression of endogenous retroviruses in mouse primordial germ cells

2014-09-01 | GSE60377 | GEO

Naïve pluripotency is associated with global DNA hypomethylation

2013-02-17 | GSE43398 | GEO

Effect of PRMT5 knockout on gene expression in epididymal white adipose tissues

Project description:In this study, we applied RNA sequencing of WT (Prmt5flox/flox) and Adiponectin-Cre driven Prmt5 knockout (Prmt5AKO) adipose tissue to uncover the molecular mechanisms underlying PRMT5 function.

2023-12-01 | GSE230565 | GEO

Genome-wide DNA methylation reprogramming in porcine primordial germ cells

Project description:DNA methylation reprogramming of primordial germ cells (PGCs) is an essential step that affects the activation and inactivation of certain genes, therefore having a direct impact on the transcriptome of an individual. In this study, we have described the methylome landscape of porcine PGCs, characterizing the genomic elements that resist methylation erasure.

2021-02-04 | E-MTAB-9326 | biostudies-arrayexpress

NaÃ¯ve pluripotency is associated with global DNA hypomethylation

Project description:Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs, in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however, we find that EGCs and ESCs exhibit equivalent global DNA methylation levels. Importantly, inhibition of Erk and Gsk3b by 2i conditions leads to pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i, and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instills a naive pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs. EGC lines were derived from E8.5 mouse embryos using three different protocols: FCS+LIF on MEFs (FCS, n = 4)), FCS+LIF on MEFs for 48 hours followed by 2i+LIF (2is, n = 4), and direct derivation into 2i+LIF (2i, n = 4). ESC lines were derived in either FCS+LIF on MEFs or in 2i+LIF conditions and once established the cell lines were also switched between the two culture environments (n = 5 for each culture condition). All cell lines were derived from genetically identical embryos.

2013-02-17 | E-GEOD-43398 | biostudies-arrayexpress

Retention of paternal epigenetic memory in the developing teleost germline [WGBS]

Project description:Two waves of DNA methylation reprogramming occur during mammalian embryogenesis; during preimplantation development and during primordial germ cell (PGC) formation. However, it is currently unclear how evolutionarily conserved these processes are. Here we characterize the DNA methylomes of zebrafish PGCs at four developmental stages and unravel retention of paternal epigenetic memory, in stark contrast with the findings in mammals. Gene expression profiling of zebrafish PGCs at same developmental stages revealed that the embryonic germline is defined by a small number of markers that display strong developmental stage-specificity and that are uncoupled from DNA methylation-mediated regulation.

2019-07-26 | GSE122722 | GEO

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