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发育性 DNA 去甲基化是神经干细胞特性和神经发生能力的决定因素。

Developmental DNA demethylation is a determinant of neural stem cell identity and gliogenic competence.

机构信息

Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 1046142, USA.

Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 10461, USA.

出版信息

Sci Adv. 2024 Aug 30;10(35):eado5424. doi: 10.1126/sciadv.ado5424. Epub 2024 Aug 28.

DOI:10.1126/sciadv.ado5424
PMID:39196941
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11352921/
Abstract

DNA methylation is extensively reconfigured during development, but the functional significance and cell type-specific dependencies of DNA demethylation in lineage specification remain poorly understood. Here, we demonstrate that developmental DNA demethylation, driven by ten-eleven translocation 1/2/3 (TET1/2/3) enzymes, is essential for establishment of neural stem cell (NSC) identity and gliogenic potential. We find that loss of all three TETs during NSC specification is dispensable for neural induction and neuronal differentiation but critical for astrocyte and oligodendrocyte formation, demonstrating a selective loss of glial competence. Mechanistically, TET-mediated demethylation was essential for commissioning neural-specific enhancers in proximity to master neurodevelopmental and glial transcription factor genes and for induction of these genes. Consistently, loss of all three TETs in embryonic NSCs in mice compromised glial gene expression and corticogenesis. Thus, TET-dependent developmental demethylation is an essential regulatory mechanism for neural enhancer commissioning during NSC specification and is a cell-intrinsic determinant of NSC identity and gliogenic potential.

摘要

DNA 甲基化在发育过程中广泛重排，但 DNA 去甲基化在谱系特化中的功能意义和细胞类型特异性依赖性仍知之甚少。在这里，我们证明了由十 - 十一易位 1/2/3（TET1/2/3）酶驱动的发育性 DNA 去甲基化对于神经干细胞（NSC）身份和神经发生潜能的建立是必不可少的。我们发现，在 NSC 特化过程中丧失所有三种 TET 对于神经诱导和神经元分化是可有可无的，但对于星形胶质细胞和少突胶质细胞的形成是至关重要的，这表明了胶质细胞能力的选择性丧失。从机制上讲，TET 介导的去甲基化对于接近主神经发育和神经胶质转录因子基因的神经特异性增强子的委托以及这些基因的诱导是必不可少的。一致地，在小鼠胚胎 NSCs 中丧失所有三种 TET 会损害神经胶质基因表达和皮质发生。因此，TET 依赖性发育性去甲基化是 NSC 特化过程中神经增强子委托的重要调节机制，是 NSC 身份和神经发生潜能的细胞内在决定因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/29f78cd6345e/sciadv.ado5424-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/bfada64c632f/sciadv.ado5424-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/ad3bf1dbd7a8/sciadv.ado5424-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/f18551a14e1c/sciadv.ado5424-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/8dfef0c44c16/sciadv.ado5424-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/db2fde834420/sciadv.ado5424-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/df6fde7f572d/sciadv.ado5424-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/67f01fea0510/sciadv.ado5424-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/2c19859b1d2a/sciadv.ado5424-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/29f78cd6345e/sciadv.ado5424-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/bfada64c632f/sciadv.ado5424-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/ad3bf1dbd7a8/sciadv.ado5424-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/f18551a14e1c/sciadv.ado5424-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/8dfef0c44c16/sciadv.ado5424-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/db2fde834420/sciadv.ado5424-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/df6fde7f572d/sciadv.ado5424-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/67f01fea0510/sciadv.ado5424-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/2c19859b1d2a/sciadv.ado5424-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f515/11352921/29f78cd6345e/sciadv.ado5424-f9.jpg

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