Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain.
Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain.
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DOI：
10.1016/j.neuron.2015.05.018
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发表时间：
2015-06-17
期刊：
影响因子：
16.2
通讯作者：
Nathans J
中科院分区：
文献类型：
--
作者：
Mo A;Mukamel EA;Davis FP;Luo C;Henry GL;Picard S;Urich MA;Nery JR;Sejnowski TJ;Lister R;Eddy SR;Ecker JR;Nathans J
神经元的多样性对哺乳动物的大脑功能至关重要，但对分子分析提出了挑战。为了解决对促进细胞类型特异性表观基因组研究的工具的需求，我们开发了第一种亲和纯化方法，以从哺乳动物中遗传定义的细胞类型中分离细胞核。我们将联合收割机这种技术与下一代测序相结合，以显示新皮层神经元的三种亚型具有高度独特的表观基因组景观。超过200，000个区域在染色质可及性和基因调控区域的DNA甲基化特征方面存在差异。通过足迹法和基序分析，预测这些区域结合不同的神经元亚型特异性转录因子。神经元表观基因组反映了过去和现在的基因表达，在发育关键基因的DNA超甲基化作为成熟神经元中的一种新的表观基因组特征出现。总之，我们的发现将神经元的功能和转录复杂性与其潜在的表观基因组多样性联系起来。
Neuronal diversity is essential for mammalian brain function but poses a challenge to molecular profiling. To address the need for tools that facilitate cell-type-specific epigenomic studies, we developed the first affinity purification approach to isolate nuclei from genetically defined cell types in a mammal. We combine this technique with next-generation sequencing to show that three subtypes of neocortical neurons have highly distinctive epigenomic landscapes. Over 200,000 regions differ in chromatin accessibility and DNA methylation signatures characteristic of gene regulatory regions. By footprinting and motif analyses, these regions are predicted to bind distinct cohorts of neuron subtype-specific transcription factors. Neuronal epigenomes reflect both past and present gene expression, with DNA hyper-methylation at developmentally critical genes appearing as a novel epigenomic signature in mature neurons. Taken together, our findings link the functional and transcriptional complexity of neurons to their underlying epigenomic diversity.