5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer's disease.
5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer's disease.
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5-羟甲基胞嘧啶在前脑类器官发育过程中受到动态调节，并在阿尔茨海默病中发生异常改变。
DOI：
10.1016/j.celrep.2021.109042
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发表时间：
2021-04-27
期刊：
影响因子：
8.8
通讯作者：
Yao B
中科院分区：
文献类型：
--
作者：
Kuehner JN;Chen J;Bruggeman EC;Wang F;Li Y;Xu C;McEachin ZT;Li Z;Chen L;Hales CM;Wen Z;Yang J;Yao B
5-羟甲基胞嘧啶（5hmC）在哺乳动物脑发育过程中经历动态变化，其失调与阿尔茨海默病（AD）有关。早期人类大脑发育过程中5hmC的动态以及它们如何促进AD病理学仍然在很大程度上未被探索。我们生成5hmC和转录组谱，包括健康前脑类器官和来自几个家族性AD患者的类器官的几个发育时间点。阶段特异性差异羟甲基化区域表现出收购或耗尽的5hmC修改整个发展阶段。此外，基因伴随增加或减少5hmC和基因表达的神经生物学或早期发育过程中，分别丰富。重要的是，我们的AD类器官证实了先前在人类AD大脑中观察到的细胞和分子表型。5hmC在AD类器官中定义的胎儿组蛋白标记和增强子中的发育编程的5hmC基因内区域中显著改变。这些数据表明，高度协调的分子系统可能在这些早期发育的AD类器官中失调。Kuehner等人使用来自健康对照的前脑类器官来研究5hmC在早期大脑发育中的动力学。此外，来自几名AD患者的类器官显示异常的5hmC模式，可能会破坏早期神经元网络，并导致AD在以后的生活中发病。
5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer’s disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids. Kuehner et al. use forebrain organoids derived from healthy controls to study the dynamics of 5hmC across early brain development. In addition, organoids derived from several AD patients reveal aberrant 5hmC patterns that could disrupt early neuronal networks and contribute to the onset of AD later in life.
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影响因子：
14.9
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