Fatty acid oxidation is required for embryonic stem cell survival during metabolic stress

Yan, Hualong; Malik, Navdeep; Kim, Young-Im; He, Yunlong; Li, Mangmang; Dubois, Wendy; Liu, Huaitian; Peat, Tyler J.; Nguyen, Joe; Tseng, Yu-Chou; Ayaz, Gamze; Alzamzami, Waseem; Chan, King C.; Andrésson, Þorkell; Tessarollo, Lino; Mock, Beverly A.; Lee, Maxwell P.; Huang, Jing

doi:10.15252/embr.202052122

Cited by 23 publications

(13 citation statements)

References 58 publications

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“…A metabolic switch is thus necessary during the developmental progression from the pre-to the post-implantation embryo. Transcriptomic and metabolic analyses have previously shown that some of the metabolic pathways enriched in the stage between the pre-and post-implantation stages, the diapause stage, include glycolysis, lipolysis, fatty acid oxidation, pyruvate, and cholesterol metabolism [23,24]. These and previous studies have also suggested that autophagy is activated in a dormant blastocyst rather than a reactivated blastocyst [25].…”

Section: Diapause Metabolismmentioning

confidence: 85%

Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State

Hussein

Balachandar

Mathieu

et al. 2022

Cells

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Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of newborns. Diapause arrests the embryo at the blastocyst stage, delaying the post-implantation development of the embryo. This months-long quiescence is reversible, in contrast to senescence that occurs in aging stem cells. Recent studies have revealed critical regulators of diapause. These findings are important since defects in the diapause state can cause a lack of regeneration and control of normal growth. Controlling this state may also have therapeutic applications since recent findings suggest that radiation and chemotherapy may lead some cancer cells to a protective diapause-like, reversible state. Interestingly, recent studies have shown the metabolic regulation of epigenetic modifications and the role of microRNAs in embryonic diapause. In this review, we discuss the molecular mechanism of diapause induction.

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Section: Diapause Metabolismmentioning

confidence: 85%

Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State

Hussein

Balachandar

Mathieu

et al. 2022

Cells

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“…Altogether, this strongly suggests that the primary consequence of ZC3H11A deficiency is in the ICM, due to perturbed metabolic regulation. The enrichment of genes associated with autophagy and apoptosis-related pathways (Figure 5A-5B) among the up-regulated genes in Zc3h11a –/– embryos could be secondary effect caused by the metabolic stress encountered by the ICM cells [32, 33].…”

Section: Resultsmentioning

confidence: 99%

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

Younis

Jouneau

Larsson

et al. 2022

Preprint

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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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“…TFCP2L1 plays a role in upregulation of Nanog ( Ye et al, 2013 ), which is also indispensable for derivation of ESCs from mouse embryos ( Silva et al, 2009 ). Interestingly, both Nanog and Tfcp2l1 can be deleted from established ESCs cultured in 2i/LIF ( Chambers et al, 2007 ; Martello et al, 2013 ; Yan et al, 2021 ), indicating compensation by the robust and redundant network of pluripotency factors that can be assembled in ESCs in vitro ( Dunn et al, 2014 ). This pathway connection may explain the failure of embryos lacking TFCP2L1 to yield ESCs and further highlights the distinct requirements for self-renewal of naïve pluripotent cells in vivo compared with established cell lines in vitro .…”

Section: Discussionmentioning

confidence: 99%

Requirement for STAT3 and its target, TFCP2L1, in self-renewal of naïve pluripotent stem cells in vivo and in vitro

et al. 2023

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We previously demonstrated gradual loss of epiblast during diapause in embryos lacking components of the LIF/IL6 receptor. Here, we explore requirement for the downstream signalling transducer and activator of transcription, STAT3 and its target, TFCP2L1, in maintenance of naïve pluripotency. Unlike conventional markers, such as NANOG, which remains high in epiblast until implantation, both STAT3 and TFCP2L1 proteins decline during blastocyst expansion, but intensify in the embryonic region after induction of diapause, as observed visually and confirmed using our image analysis pipeline, consistent with our previous transcriptional expression data. Embryos lacking STAT3 or TFCP2L1 underwent catastrophic loss of most of the inner cell mass during the first few days of diapause, implicating involvement of signals in addition to LIF/IL6 for sustaining naïve pluripotency in vivo. By blocking MEK/ERK signalling from the morula stage we could derive embryonic stem cells with high efficiency from STAT3 null embryos, but not those lacking TFCP2L1, suggesting a hitherto unknown additional role for this essential STAT3 target in transition from embryo to embryonic stem cells in vitro.

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Fatty acid oxidation is required for embryonic stem cell survival during metabolic stress

Cited by 23 publications

References 58 publications

Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State

Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State

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

Requirement for STAT3 and its target, TFCP2L1, in self-renewal of naïve pluripotent stem cells in vivo and in vitro

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