DNA Methylome and 3D Chromatin Landscape of Cell Types Across the Mouse Brain [11K_201022]

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. Apply snmC-seq3 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 (11K).

阐明哺乳动物大脑的细胞架构，对于理解其多样的功能与复杂的动物行为至关重要。本研究受美国国家精神卫生研究院（NIMH）与美国国家神经疾病和中风研究所（NINDS）资助，作为大脑计划细胞普查网络（BICCN）的组成部分，小鼠脑图谱表观基因组学中心（CEMBA）对成年雄性P56龄C57BL/6J小鼠全脑的117个脑功能区开展了单细胞核甲基化测序（single nucleus methylation sequencing）。在各主要脑区中，我们鉴定得到了不同的细胞簇，并构建了层级分类体系。这些细胞簇既包含已被认知的主要脑细胞类型，也涵盖潜在的亚型。我们利用该数据集解析了表观基因组特征，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（single cell methylome）与同一脑区来源的单细胞基因表达及染色质可及性图谱（chromatin accessibility profiles）进行整合，以进一步鉴定多种神经元细胞类型的潜在增强子（enhancer）及其靶基因。通过脑区空间比较分析，我们发现同一皮层层内的兴奋性神经元簇存在空间特异性；同时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（transcription factor）。本数据集明确了小鼠脑细胞类型与空间异质性的全貌，及其背后的调控性表观基因组基础。本子系列针对117个脑功能区采用单细胞核甲基化测序3（snmC-seq3）技术以解析成年小鼠脑的表观基因组全貌，包含一项针对脑区（11K）的单细胞核甲基化测序实验。