Center for Multiomic Human Brain Cell Atlas

摘要 了解细胞的特性及其在人脑不同区域的空间分布是一个 尝试整合生理、行为、神经化学和分子数据时的基本步骤。在… 目前，虽然人类大脑中存在的细胞类型的主要类别已经从分子上定义， 这些类别中的不同亚型及其位置还远未被理解。基因表达 驱动细胞程序和状态，这些程序和状态是不同大脑功能的基础。开放染色质和修饰组蛋白 标记控制细胞类型特定基因表达模式的基因调控元件。胞嘧啶DNA 甲基化(MC)是一种稳定的表观基因组特征，在有丝分裂后细胞的一生中持续存在， 定义他们的手机身份。单细胞基因表达、染色质开放图谱和DNA甲基化分析 已经成功地用于在异种组织中以无偏见的方式识别不同的细胞类型 包括人类的大脑。这个UM1建议建立在我们早期在小鼠脑图谱上取得的成功的基础上 在100个解剖结构的单细胞水平上制作详细的单细胞、多染色体和空间细胞图 定义了人脑中的区域。分析人类大脑样本将允许发现独特的基因 每种分子定义的细胞类型的表达模式，识别它们的空间组织，以及它们的特定 非编码DNA调控区。表观基因组特征和转录特征之间的多模式整合 将允许识别新的细胞类型和独特的细胞类型标记，这些标记将迅速提供给 整个社区。该UM1项目还将为以前无法获得的基因获取提供新的工具 以及促进与神经精神和精神疾病相关的遗传变异的功能分析 神经紊乱。

Abstract Understanding cell identities and their spatial distributions throughout different regions of the human brain is a fundamental step when trying to integrate physiological, behavioral, neurochemical and molecular data. At present, although major categories of the cell-types present in the human brain have been defined molecularly, the different subtypes within these categories along with their locations are far from understood. Gene expression drives cell programs and states that underlie distinct brain functions. Open chromatin and modified histones mark gene-regulatory elements that control cell type-specific gene expression patterns. Cytosine DNA methylation (mC) is a stable epigenomic signature that persists in post-mitotic cells throughout their lifetime, defining their cellular identity. Single-cell gene expression, open chromatin profiles and DNA methylation assays have been successfully used to identify distinct cell types in an unbiased fashion in heterogeneous tissues including the human brain. This UM1 proposal builds on our earlier successes in mouse brain mapping to produce detailed single-cell multimomic and spatial cell maps at the single-cell level across 100 anatomically defined regions in the human brain. Profiling human brain samples will permit the discovery of unique gene expression patterns for each molecularly-defined cell type, identify their spatial organization, and their specific non-coding DNA regulatory regions. Multi-modal integration between epigenomic and transcriptomic signatures will allow the identification of new cell types and unique cell-type markers that will rapidly be made available to the entire community. This UM1 project will also provide new tools for genetic access of previously inaccessible brain regions as well as facilitate the functional analysis of genetic variants associated with neuropsychiatric and neurological disorders.