Eif2s2 deficiency causes oocyte arrest at the early diplotene stage and apoptosis in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1099574 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28641015_1.fastq.gz | Fastqsanger.gz | |||
| SRR28641015_2.fastq.gz | Fastqsanger.gz | |||
| SRR28641016_1.fastq.gz | Fastqsanger.gz | |||
| SRR28641016_2.fastq.gz | Fastqsanger.gz |
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Project description:Eukaryotic translation initiation factor 2 subunit 2 (EIF2S2), a subunit of the heterotrimeric G protein EIF2, is involved in the initiation of translation. Our findings demonstrate that the depletion of Eif2s2 in premeiotic germ cells causes oocyte arrest at the pachytene and early diplotene stages at 1 day postpartum (dpp) and 5 dpp, respectively, and eventually leads to oocyte apoptosis and failure of primordial follicle formation. Further studies reveal that Eif2s2 deletion downregulates homologous recombination-related and mitochondrial fission-related protein levels, and upregulates the integrated stress response-related proteins and mRNA levels. Consistently, Eif2s2 deletion significantly decreases the expression of dictyate genes and compromises mitochondrial function, characterized by elongated shapes, decreased ATP levels and mtDNA copy number, along with an excessive accumulation of reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, DNA damage response and proapoptotic protein levels increase, while anti-apoptotic protein levels decrease in Eif2s2-deleted mice. An increase in oocytes with positive cleaved-Caspase-3 and TUNEL signals, alongside reduced Lamin B1 intensity, further indicates oocyte apoptosis. Collectively, Eif2s2 deletion in premeiotic germ cells causes oocyte meiotic arrest at the early diplotene stage by impairing homologous recombination, and eventually leads to oocyte apoptosis mainly through the downregulation of mitochondrial fission-related proteins, ROS accumulation and subsequent DNA damage.
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Project description:Mutations in translation initiation factors are associated with premature ovarian insufficiency. Here, we used signle-cell RNA sequencing method to investigate the effect of Eif2s2 deletion in premeiotic germ-cells on primordial formation.
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Project description:Dramatic changes in chromatin structure and histone modification occur during oocyte growth, as well as a global cessation of transcription. The role of histone modifications in these processes is poorly understood. We report the effect of conditionally deleting Hdac1 and Hdac2 on oocyte development. Deleting either gene has little or no effect on oocyte development, whereas deleting both genes results in follicle development arrest at the secondary follicle stage. This developmental arrest is accompanied by substantial perturbation of the transcriptome and a global reduction in transcription even though histone acetylation is markedly increased. There is no apparent change in histone repressive marks but there is a pronounced decrease in histone H3K4 methylation, an activating mark. The decrease in H3K4 methylation is likely due to increased expression of Kdm5b because RNAi-mediated targeting of Kdm5b in double mutant oocytes results in an increase in H3K4 methylation. An increase in TRP53 acetylation also occurs in mutant oocytes and may contribute to the observed increased incidence of apoptosis. Taken together, these results suggest seminal roles of acetylation of histone and non-histone proteins in oocyte development. We used microarrays to detail the global programme of gene expression underlying oocyte development and identified distinct classes of regulated genes during this process.
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Project description:Dramatic changes in chromatin structure and histone modification occur during oocyte growth, as well as a global cessation of transcription. The role of histone modifications in these processes is poorly understood. We report the effect of conditionally deleting Hdac1 and Hdac2 on oocyte development. Deleting either gene has little or no effect on oocyte development, whereas deleting both genes results in follicle development arrest at the secondary follicle stage. This developmental arrest is accompanied by substantial perturbation of the transcriptome and a global reduction in transcription even though histone acetylation is markedly increased. There is no apparent change in histone repressive marks but there is a pronounced decrease in histone H3K4 methylation, an activating mark. The decrease in H3K4 methylation is likely due to increased expression of Kdm5b because RNAi-mediated targeting of Kdm5b in double mutant oocytes results in an increase in H3K4 methylation. An increase in TRP53 acetylation also occurs in mutant oocytes and may contribute to the observed increased incidence of apoptosis. Taken together, these results suggest seminal roles of acetylation of histone and non-histone proteins in oocyte development. We used microarrays to detail the global programme of gene expression underlying oocyte development and identified distinct classes of regulated genes during this process. Total RNA was extracted from 80 oocytes isolated from mice 12 days-of-age using the PicoPure RNA kit (Arcturus), amplified with the Ovation Pico WTA system (NuGen), and then fragmented and labeled with the FL-OvationTM cDNA Biotin Module V2 (NuGen). Four independent biological replicates were hybridized to Affymetrix GeneChip Mouse 1.1 ST microarrays (http://www.affymetrix.com/). Raw microarray data were analyzed as previously described using MAS5, GeneSpring v7, SAM and EASE software (56). A 1.4-fold cutoff was used for EASE analysis; four biological replicates provide sufficient statistical power and confidence to detect a 1.4-fold change in transcript abundance
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