Biological signal recording enables the study of molecular inputs experienced throughout cellular history. However, current methods are limited in their ability to scale up beyond a single signal in mammalian contexts. Here, we develop an approach using a hyper-efficient dCas12a base editor for multi-signal parallel recording in human cells. We link signals of interest to expression of guide RNAs to catalyze specific nucleotide conversions as a permanent record, enabled by Cas12’s guide-processing abilities. We show this approach is plug-and-play with diverse biologically relevant inputs and extend it for more sophisticated applications, including recording of time-delimited events and history of chimeric antigen receptor T cells’ antigen exposure. We also demonstrate efficient recording of up to four signals in parallel on an endogenous safe-harbor locus. This work provides a versatile platform for scalable recording of signals of interest for a variety of biological applications.

生物信号记录可以研究整个细胞历史中经历的分子输入。然而，目前的方法在哺乳动物环境中扩展到单一信号之外的能力有限。在这里，我们开发了一种使用超高效 dCas12a 碱基编辑器在人体细胞中进行多信号并行记录的方法。我们将感兴趣的信号与引导 RNA 的表达联系起来，以催化特定的核苷酸转化作为永久记录，这由 Cas12 的引导处理能力实现。我们展示了这种方法是即插即用的，具有多种生物学相关输入，并将其扩展到更复杂的应用，包括记录时限事件和嵌合抗原受体 T 细胞抗原暴露的历史。我们还演示了在内生安全港轨迹上并行最多四个信号的有效记录。这项工作为各种生物应用的感兴趣信号的可扩展记录提供了一个多功能平台。