An integrated genome-wide multi-omics analysis of gene expression dynamics in the preimplantation mouse embryo

Israel, Steffen; Ernst, Markus; Psathaki, Olympia E.; Drexler, Hannes C.A.; Casser, Ellen; Suzuki, Yutaka; Makałowski, Wojciech; Boiani, Michele; Fuellen, Georg; Taher, Leila

doi:10.1038/s41598-019-49817-3

Cited by 45 publications

(70 citation statements)

References 87 publications

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“…The question of the role of control of AGO levels and the relationship between miRNA abundance and AGO levels in mammalian oocytes remains open. At mRNA level, Ago2 and Ago3 transcripts are the most abundant ones in mouse oocytes ( Supplementary Figure S5 ) while recent proteomic analysis identified AGO1 and AGO2 proteins ( 68 ). Our data presented here suggest that one should also consider Ago2 transcript turnover as a factor influencing the abundance of AGO2.…”

Section: Discussionmentioning

confidence: 99%

“…It remains to be investigated how AGO and miRNA levels are inter-related and how AGO expression is controlled in mammalian oocytes, as AGO protein levels may be a significant factor. It should be noted that miR-27a in porcine oocytes ( 67 ) and miR-130b in bovine oocytes ( 68 ) were proposed to be active and important; however, there is no strong evidence supporting these claims as abundance of these miRNAs and reporter repression by endogenous miRNA levels have not been assessed. Therefore, whether these miRNAs represent unique adaptations that are functional exceptions to the rule remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA dilution during oocyte growth disables the microRNA pathway in mammalian oocytes

Kataruka

Modrák

Kinterová

et al. 2020

Nucleic Acids Research

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Abstract MicroRNAs (miRNAs) are ubiquitous small RNAs guiding post-transcriptional gene repression in countless biological processes. However, the miRNA pathway in mouse oocytes appears inactive and dispensable for development. We propose that marginalization of the miRNA pathway activity stems from the constraints and adaptations of RNA metabolism elicited by the diluting effects of oocyte growth. We report that miRNAs do not accumulate like mRNAs during the oocyte growth because miRNA turnover has not adapted to it. The most abundant miRNAs total tens of thousands of molecules in growing (∅ 40 μm) and fully grown (∅ 80 μm) oocytes, a number similar to that observed in much smaller fibroblasts. The lack of miRNA accumulation results in a 100-fold lower miRNA concentration in fully grown oocytes than in somatic cells. This brings a knock-down-like effect, where diluted miRNAs engage targets but are not abundant enough for significant repression. Low-miRNA concentrations were observed in rat, hamster, porcine and bovine oocytes, arguing that miRNA inactivity is not mouse-specific but a common mammalian oocyte feature. Injection of 250,000 miRNA molecules was sufficient to restore reporter repression in mouse and porcine oocytes, suggesting that miRNA inactivity comes from low-miRNA abundance and not from some suppressor of the pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA dilution during oocyte growth disables the microRNA pathway in mammalian oocytes

Kataruka

Modrák

Kinterová

et al. 2020

Nucleic Acids Research

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“…(B). Abundance profile of Cops3 mRNA and COPS3 protein, each measured by two independent methods; data are presented as means and standard deviations (for RNA, 100 oocytes or embryos per stage in two replicates; for protein, 200-600 oocytes or embryos per stage in three proteomic replicates, and at least 3 oocytes or embryos per stage for immunofluorescence; transcriptome/proteome datasets are extracted from 26 and are provided here in Supplementary Tables 1 and 2). (C).…”

Section: Resultsmentioning

confidence: 99%

“…Proteome and transcriptome analysis of oocytes, zygotes and preimplantation embryos. To assess the developmental profile of COPS3 we made use of already existing datasets that we had published previously 22,26 . To assess the immediate impact of TRIM21-mediated COPS3 depletion on the protein composition of the 2-cell stage we generated a new proteomic dataset using the same pipeline as described in 22 .…”

Section: Methodsmentioning

confidence: 99%

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Israel

Drexler

Fuellen

et al. 2021

Preprint

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Investigations of genes required in early mammalian development are complicated by protein deposits of maternal products, which continue to operate after the gene locus has been disrupted. This leads to an underestimation of the number of genes known to be needed during the embryonic phase of cellular totipotency (up to the 4-cell stage). Here, we expose a critical role of the gene Cops3 by showing that it protects genome integrity during the 2-cell stage of mouse embryo development, in contrast to the previous functional assignment at postimplantation. This new role is mediated by a large, stable and hitherto overlooked deposit of maternal protein. Since protein abundance and stability defeat prospects of DNA- or RNA-based gene inactivation, we adopted a protein strategy of gene inactivation: antigen masking or TRIM21-mediated proteasomal degradation of COPS3. Both resulted in 2-cell embryo lethality, but the expected degradation remained outstanding, because the major fraction of the total COPS3 is secluded in a submembrane cortical rim that withstands extraction with detergent, thereby exposing a soluble vs. insoluble fraction of COPS3, which we ascribe with distinct functional properties. In mechanistic terms, transcriptomic and metabolic analyses reveal that soluble COPS3 is involved in several processes, which, however, converge on DNA endoreduplication and the accumulation of DNA strand breaks in the 2-cell nucleus, where the minor soluble fraction of COPS3 is placed. Thus, we have shown the critical role of maternal protein deposits in development, and we have also highlighted the distinction between the site of accumulation (cell cortex) and point of use (nucleus), which is a dimension of the protein-based strategies of gene inactivation not yet fully appreciated.

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“…Accordingly, they are crucial contributors to spermiogenesis post transcriptional cessation, since they provide a stable alternative to linear mRNA templates for protein translation (Tang et al, 2020). Transmitted sperm-circRNAs could likewise contribute to translation post fertilization, yet the unconventional lattice-state of ribosomes preventing normal rates of translation post transcription (Israel et al, 2019) accompanied by a rapid increase in proteins of the ubiquitine/proteasome pathway (Wang et al, 2010) make this unlikely. Never the less a study on human sperm detected abundant levels of circRNA with predicted regulatory function of early developmental genes in sperm heads, suggesting transmission and function post fertilization (Chioccarelli et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Single paternal Dexamethasone challenge programs offspring metabolism and reveals circRNAs as novel candidates in RNA-mediated inheritance

Gapp

Parada

Groß

et al. 2021

Preprint

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Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Studies in mice suggests germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain unknown. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid Dexamethasone, affects the RNA payload of post-meiotic mature sperm as soon as 3 hours post exposure, challenging the prevalent view that epididymal transit is required to alter sperm RNA. It further impacts early embryonic transcriptional trajectories, as determined by single embryo sequencing, and metabolism in the offspring. Importantly, we show persistent regulation of tRNA fragments in sperm and the descendant 2-cell-embryos, suggesting actual transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in the previously underconsidered class of sperm circRNAs, and their targets in the early embryo, highlighting this class as a novel candidate in RNA-mediated inheritance.

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An integrated genome-wide multi-omics analysis of gene expression dynamics in the preimplantation mouse embryo

Cited by 45 publications

References 87 publications

MicroRNA dilution during oocyte growth disables the microRNA pathway in mammalian oocytes

MicroRNA dilution during oocyte growth disables the microRNA pathway in mammalian oocytes

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Single paternal Dexamethasone challenge programs offspring metabolism and reveals circRNAs as novel candidates in RNA-mediated inheritance

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