Decades of research have established that mammalian transcription factors (TFs) bind to each gene’s regulatory regions and cooperatively control tissue specificity, timing, and intensity of gene transcription. Mapping the combination of TF binding sites genome wide is critically important for understanding functional genomics. Here, we report a technique to measure TFs’ binding sites on the human genome with a near single-base resolution by footprinting with deaminase (FOODIE) on a single-molecule and single-cell basis. Single-molecule sequencing reads after enzymatic deamination allow detection of the TF binding fraction on a particular footprint and the binding cooperativity of any two adjacent TFs, which can be either positive or negative. As a newcomer of single-cell genomics, single-cell FOODIE enables the detection of cell-type-specific TF footprints in a pure cell population in a heterogeneous tissue, such as the brain. We found that genes carrying out a certain biological function together in a housing-keeping correlated gene module (CGM) or a tissues-specific CGM are coordinated by shared TFs in the gene’s promoters and enhancers, respectively. Scalable and cost-effective, FOODIE allows us to create an open FOODIE database for cell lines, with applicability to human tissues and clinical samples.

中文翻译：

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用脱氨酶对转录因子进行全基因组单细胞和单分子足迹分析


数十年的研究已经确定，哺乳动物转录因子 （TFs） 与每个基因的调控区域结合，并协同控制基因转录的组织特异性、时间和强度。在全基因组范围内绘制 TF 结合位点的组合对于理解功能基因组学至关重要。在这里，我们报道了一种通过在单分子和单细胞基础上用脱氨酶 （FOODIE） 足迹来测量 TFs 在人类基因组上以接近单碱基分辨率的结合位点的技术。酶促脱氨后的单分子测序读长可以检测特定足迹上的 TF 结合组分以及任意两个相邻 TF 的结合协同性，可以是阳性或阴性。作为单细胞基因组学的新成员，单细胞 FOODIE 能够检测异质组织（如大脑）中纯细胞群中的细胞类型特异性 TF 足迹。我们发现，在住房保持相关基因模块 （CGM） 或组织特异性 CGM 中一起执行某种生物学功能的基因分别由基因启动子和增强子中的共享 TFs 协调。FOODIE 可扩展且具有成本效益，使我们能够为细胞系创建一个开放的 FOODIE 数据库，适用于人体组织和临床样本。