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bioRxiv · 10.1101/2022.09.14.508037

Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes

Younis, S.·Jouneau, A.·Larsson, M.·Oudin, J.-F.·Brochard, V.·Andersson, L.
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Abstract

ZC3H11A is a stress-induced mRNA binding protein required for efficient growth of nuclear-replicating viruses, while being dispensable for the viability of cultured human cells. The cellular functions of ZC3H11A during embryo development are unknown. Here we report the generation and phenotypic characterization of Zc3h11a knock-out mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a-/- embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a-/- embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a-/- embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. Furthermore, CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Altogether, the results show that ZC3H11A is participating in export and post-transcriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional knock-out did not lead to obvious phenotypic defects.

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Younis, S., Jouneau, A., Larsson, M., Oudin, J.-F., Brochard, V., Andersson, L.. 2022-09-16. Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes. https://doi.org/10.1101/2022.09.14.508037

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