Identifying gene regulatory targets of nuclear proteins in tissues remains a challenge. Here we describe intranuclear Cellular Indexing of Transcriptomes and Epitopes (inCITE-seq), a scalable method for measuring multiplexed intranuclear protein levels and the transcriptome in parallel in thousands of cells, enabling joint analysis of TF levels and gene expression in vivo. We apply inCITE-seq to characterize cell state-related changes upon pharmacological induction of neuronal activity in the mouse brain. Modeling gene expression as a linear combination of quantitative protein levels revealed the genome-wide effect of each TF and recovered known targets. Cell type-specific genes associated with each TF were co-expressed as distinct modules that each corresponded to positive or negative TF levels, showing that our approach can disentangle relative contributions of TFs to gene expression and add interpretability to gene networks. InCITE-seq can illuminate how combinations of nuclear proteins shape gene expression in native tissue contexts, with direct applications to solid or frozen tissues and clinical specimens.

中文翻译：

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核内蛋白质和基因表达的同时单细胞测量

鉴定组织中核蛋白的基因调控靶标仍然是一个挑战。在这里，我们描述了在tranuclear Ç ellular我的ndexing Ť ranscriptomes和ë pitopes（煽动-SEQ）中，用于测量复核内蛋白水平的可扩展的方法和在成千上万的细胞在平行转录，使TF水平和基因表达的联合分析中体内。我们应用inCITE-seq来表征药理学诱导小鼠大脑神经元活动后细胞状态相关的变化。将基因表达建模为定量蛋白质水平的线性组合，揭示了每个TF和回收的已知靶标在全基因组范围内的作用。与每个TF相关的细胞类型特异性基因作为不同的模块共表达，每个模块分别对应于阳性或阴性TF水平，这表明我们的方法可以消除TF对基因表达的相对贡献，并为基因网络增加可解释性。InCITE-seq可以阐明核蛋白的组合如何在天然组织环境中影响基因表达，并直接应用于固体或冷冻组织以及临床标本。