DNA Methylome and 3D Chromatin Landscape of Cell Types Across the Mouse Brain [10B_190725]

Illustrating the cellular architecture of the mammalian brain is critical to understanding its diverse functions and complex animal behaviors. With support from NIMH and NINDS as part of the BRAIN Initiative Cell Census Network (BICCN), the Center for Epigenomics of the Mouse Brain Atlas (CEMBA) applied single nucleus methylation sequencing in 117 brain funtional regions across the whole adult male P56 C57BL/6J mouse brain. In each major brain regions, we identified distinct cell clusters and formed them in a hierarchical taxonomy. These clusters include known primary brain cell types and possible sub-types. We use these data to identify the epigenomic characteristics and to define specific regulatory elements for each cell cluster. We integrate the single cell methylome with single cell gene expression and chromatin accessibility profiles from the same brain region to further identify potential enhancers and their corresponding genes for several neuronal cell types. By brain region spacial comparisons, we found spatial specificity among excitatory neuronal clusters within the same cortical layer. We identify brain-region-specific transcription factors that may regulate cortical region development of excitatory neurons. These data define the landscape of cell type and spatial heterogeneity in the mouse brain and the underlining regulatory epigenomic basis. Overall design: Apply snmC-seq2 to 117 brain functional regions to identify epigenomic landcape of the adult mouse brain, this subseries consists of one single nucleus methylation sequencing experiment of brain region (10B).

阐明哺乳动物大脑的细胞架构，对于理解其多样功能与复杂动物行为至关重要。本研究获得美国国家精神卫生研究院（National Institute of Mental Health, NIMH）与美国国家神经疾病和中风研究所（National Institute of Neurological Disorders and Stroke, NINDS）资助，作为大脑计划细胞普查网络（BRAIN Initiative Cell Census Network, BICCN）的组成部分，小鼠大脑表观基因组学图谱中心（Center for Epigenomics of the Mouse Brain Atlas, CEMBA）对成年雄性P56龄C57BL/6J小鼠全脑的117个脑功能区域开展了单细胞核甲基化测序（single nucleus methylation sequencing）。在各主要脑区中，研究团队鉴定出特征各异的细胞簇，并构建了层级分类体系。这些细胞簇涵盖了已知的主要脑细胞类型及潜在亚型。本研究利用上述数据解析了表观基因组学特征，并为每个细胞簇定义了特异性调控元件。我们将单细胞甲基化组与同一脑区的单细胞基因表达、染色质可及性图谱进行整合，进一步鉴定了多种神经元细胞类型的潜在增强子及其对应靶基因。通过脑区空间比较分析，研究团队发现同一皮层层内的兴奋性神经元簇具有空间特异性，并鉴定出可能调控兴奋性神经元皮层区域发育的脑区特异性转录因子。上述数据刻画了小鼠大脑中细胞类型与空间异质性的全貌，并揭示了其潜在的调控表观基因组学基础。整体实验设计：对117个脑功能区域采用snmC-seq2技术以解析成年小鼠大脑的表观基因组图谱；本次子系列仅包含脑区10B的单细胞核甲基化测序实验。