DNA methylation atlas of the mouse brain at single-cell resolution.
DNA methylation atlas of the mouse brain at single-cell resolution.
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单细胞分辨率的小鼠大脑 DNA 甲基化图谱。
DOI：
10.1038/s41586-020-03182-8
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发表时间：
2021-10
期刊：
影响因子：
64.8
通讯作者：
Ecker JR
中科院分区：
文献类型：
--
作者：
Liu H;Zhou J;Tian W;Luo C;Bartlett A;Aldridge A;Lucero J;Osteen JK;Nery JR;Chen H;Rivkin A;Castanon RG;Clock B;Li YE;Hou X;Poirion OB;Preissl S;Pinto-Duarte A;O'Connor C;Boggeman L;Fitzpatrick C;Nunn M;Mukamel EA;Zhang Z;Callaway EM;Ren B;Dixon JR;Behrens MM;Ecker JR
哺乳动物脑细胞在基因表达、解剖学和功能方面表现出显著的多样性，但对这种广泛异质性背后的调控DNA景观知之甚少。在这里，我们通过应用单核DNA甲基化测序对来自小鼠皮层、海马、纹状体、苍白球和嗅觉区的45个区域的103，982个核（包括95，815个神经元和8，167个非神经元细胞）进行了全面评估。我们确定了161个具有不同空间位置和投影目标的细胞簇。我们构建了这些表观遗传类型的分类学，注释与签名基因，调控元件和转录因子。这些功能表明潜在的监管景观支持假定的细胞类型的分配，并揭示了重复使用的监管机构在兴奋性和抑制性细胞确定亚型。皮层和海马兴奋性神经元的DNA甲基化景观沿着空间梯度连续变化。使用这个深度数据集，我们构建了一个人工神经网络模型，可以精确预测单个神经元细胞类型和大脑区域空间位置。高分辨率DNA甲基化组与单核染色质可及性数据的整合使得能够预测所有鉴定的细胞类型的高置信度增强子-基因相互作用，随后通过细胞类型特异性染色质构象捕获实验进行验证。通过结合来自单个细胞核的多组学数据集（DNA甲基化，染色质接触和开放染色质）并注释小鼠大脑中数百种细胞类型的调控基因组，我们的DNA甲基化图谱为整个小鼠大脑的神经元多样性和空间组织建立了表观遗传基础。使用单核DNA甲基化测序对来自小鼠皮层、海马、纹状体、苍白球和嗅觉区的45个区域的表观基因组进行全面调查，能够识别具有不同位置和投射靶点的161个细胞簇，并提供了对神经元多样性和空间调节的调控景观的见解。
Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data enabled prediction of high-confidence enhancer–gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum. A comprehensive survey of the epigenome from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas using single-nucleus DNA methylation sequencing enables identification of 161 cell clusters with distinct locations and projection targets and provides insights into the regulatory landscape underlying neuronal diversity and spatial regulation.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
64.5
作者：
Dekker J;Mirny L
通讯作者：
Mirny L
影响因子：
25
作者：
Guo, Junjie U.;Su, Yijing;Shin, Joo Heon;Shin, Jaehoon;Li, Hongda;Xie, Bin;Zhong, Chun;Hu, Shaohui;Le, Thuc;Fan, Guoping;Zhu, Heng;Chang, Qiang;Gao, Yuan;Ming, Guo-li;Song, Hongjun
通讯作者：
Song, Hongjun
影响因子：
48
作者：
Lee, Dong-Sung;Luo, Chongyuan;Ecker, Joseph R.
通讯作者：
Ecker, Joseph R.
影响因子：
64.8
作者：
Gorkin, David U.;Barozzi, Iros;Ren, Bing
通讯作者：
Ren, Bing