Stem Cell Chromatin Lab, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
Nat Struct Mol Biol. 2024 Oct;31(10):1625-1639. doi: 10.1038/s41594-024-01313-7. Epub 2024 May 23.
Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET-transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease.
休眠是许多生命形式通过世代和应激条件进行繁殖的必要生物过程。许多哺乳动物的早期胚胎在子宫内可以以休眠状态(称为滞育)保存数周到数月,这种状态可以通过 mTOR 抑制在体外诱导。在休眠的沉默基因组景观中保护原始细胞身份的细胞策略尚不清楚。在这里,我们表明,保护顺式调控元件免受沉默是维持休眠状态多能性的关键。我们揭示了一个 TET-转录因子轴,其中 TET 介导的 DNA 去甲基化和募集甲基敏感转录因子 TFE3 在休眠状态转变过程中驱动转录惰性染色质适应。TET 活性的扰动会损害休眠中小鼠胚胎的多能性和存活率,而增强 TET 活性则会提高存活率。我们的研究结果揭示了休眠细胞传播细胞身份的重要机制,对再生和疾病具有重要意义。
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