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TET 酶活性在胚胎休眠期间保障多能性。

TET activity safeguards pluripotency throughout embryonic dormancy.

机构信息

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.

出版信息

Nat Struct Mol Biol. 2024 Oct;31(10):1625-1639. doi: 10.1038/s41594-024-01313-7. Epub 2024 May 23.


DOI:10.1038/s41594-024-01313-7
PMID:38783076
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11479945/
Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a879/11479945/799c52e4cced/41594_2024_1313_Fig18_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a879/11479945/8d960972f5f6/41594_2024_1313_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a879/11479945/5e481ddf19c6/41594_2024_1313_Fig9_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a879/11479945/8aafab703867/41594_2024_1313_Fig15_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a879/11479945/799c52e4cced/41594_2024_1313_Fig18_ESM.jpg

相似文献

[1]
TET activity safeguards pluripotency throughout embryonic dormancy.

Nat Struct Mol Biol. 2024-10

[2]
TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling.

Nature. 2016-10-19

[3]
Tet inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development.

Nat Commun. 2019-9-20

[4]
Combinatorial microRNA activity is essential for the transition of pluripotent cells from proliferation into dormancy.

Genome Res. 2024-5-15

[5]
Rinf Regulates Pluripotency Network Genes and Tet Enzymes in Embryonic Stem Cells.

Cell Rep. 2019-8-20

[6]
Functionally distinct roles for TET-oxidized 5-methylcytosine bases in somatic reprogramming to pluripotency.

Mol Cell. 2021-2-18

[7]
TET family regulates the embryonic pluripotency of porcine preimplantation embryos by maintaining the DNA methylation level of .

Epigenetics. 2020-11

[8]
TET enzymes, DNA demethylation and pluripotency.

Biochem Soc Trans. 2019-6-17

[9]
Loss of Tet hydroxymethylase activity causes mouse embryonic stem cell differentiation bias and developmental defects.

Sci China Life Sci. 2024-10

[10]
PRDM14 promotes active DNA demethylation through the ten-eleven translocation (TET)-mediated base excision repair pathway in embryonic stem cells.

Development. 2013-12-11

引用本文的文献

[1]
A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.

Nat Aging. 2025-6-30

[2]
mTOR activity paces human blastocyst stage developmental progression.

Cell. 2024-11-14

本文引用的文献

[1]
Combinatorial microRNA activity is essential for the transition of pluripotent cells from proliferation into dormancy.

Genome Res. 2024-5-15

[2]
FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.

Nat Cell Biol. 2024-2

[3]
mA RNA methylation orchestrates transcriptional dormancy during paused pluripotency.

Nat Cell Biol. 2023-9

[4]
Young LINE-1 transposon 5' UTRs marked by elongation factor ELL3 function as enhancers to regulate naïve pluripotency in embryonic stem cells.

Nat Cell Biol. 2023-9

[5]
H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function.

Nat Struct Mol Biol. 2023-7

[6]
Single-molecule footprinting identifies context-dependent regulation of enhancers by DNA methylation.

Mol Cell. 2023-3-2

[7]
Species-specific rewiring of definitive endoderm developmental gene activation via endogenous retroviruses through TET1-mediated demethylation.

Cell Rep. 2022-12-13

[8]
Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation.

Nat Genet. 2022-12

[9]
Small Molecule Inhibitors of TET Dioxygenases: Bobcat339 Activity Is Mediated by Contaminating Copper(II).

ACS Med Chem Lett. 2022-4-21

[10]
The control of transcriptional memory by stable mitotic bookmarking.

Nat Commun. 2022-3-4

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