Chromatin accessibility and RNA expression in E14.5 mouse neurons

The differential activity of transcription factors (TFs) manifests in a differential genome activation in different cell lineages and cell types. Here, we have mapped mRNA expression and accessible chromatin regions in single cells derived from the developing mouse CNS. We first defined a reference set of features for scATAC-seq read quantitation across samples, allowing comparison of chromatin accessibility between brain regions and cell types directly. Second, we integrated the scRNA and scATAC data to form a unified resource of transcriptome and chromatin accessibility landscape for the cell types in diencephalon to anterior hindbrain in E14.5 mouse embryo. We show that both the chromatin accessibility and transcriptome can be used as basis for clustering and cell type definition, with high concordance. Hierarchical clustering by the similarity in genome activation reveals complex interrelationships between the cell types derived from different anteroposterior domains of the E14.5 CNS. Further work is required to describe the fraction of genome activation resulting from the activity of patterning genes and the fraction activated by the cell fate selection regulators.转录因子（transcription factors, TFs）的差异活性，体现为不同细胞谱系与细胞类型间的基因组差异化激活。本研究对发育中的小鼠中枢神经系统（Central Nervous System, CNS）来源的单细胞，完成了mRNA表达谱与染色质开放区域的图谱绘制。首先，我们为跨样本的单细胞转座酶可及性测序（single-cell Assay for Transposase-Accessible Chromatin using sequencing, scATAC-seq）读段定量定义了一套特征参考集，可直接实现不同脑区与细胞类型间染色质可及性的比较。其次，我们整合了单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）与scATAC-seq数据，构建了针对E14.5天小鼠胚胎间脑至前菱脑区域细胞类型的转录组与染色质可及性全景统一资源库。研究表明，染色质可及性与转录组均可作为细胞聚类与细胞类型鉴定的基础，且二者具有高度一致性。基于基因组激活相似性的层级聚类，揭示了E14.5天小鼠中枢神经系统不同前后轴区域来源的细胞类型间存在复杂的相互关联。未来仍需进一步研究，以厘清模式构建基因活性所介导的基因组激活占比，与细胞命运选择调控因子所激活的基因组激活比例。