Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues.

细胞分化和功能在多个基因调控层面受到调控，包括通过染色质可及性的变化来调节基因表达。然而，分化是一个异步过程，排除了对导致细胞命运承诺的调节事件的时间理解。在这里，我们开发了同步高通量 ATAC 和 RNA 表达与测序 (SHARE-seq)，这是一种高度可扩展的方法，用于测量同一单细胞中的染色质可及性和基因表达，适用于不同的组织。使用来自小鼠皮肤的 34,774 个关节轮廓，我们开发了一种计算策略来识别顺式调节相互作用并定义与超级增强子显着重叠的调节染色质 (DORC) 域。在谱系承诺期间，DORC 的染色质可及性先于基因表达，这表明染色质可及性的变化可能为谱系承诺准备细胞。我们通过计算推断染色质潜力作为染色质谱系引发的定量测量，并用它来预测细胞命运结果。SHARE-seq 是一个可扩展的平台，用于研究组织中不同细胞的调节回路。