PROJECT SUMMARY The accurate description of cellular states—be it on the genomic, transcriptomic, or proteomic level—has been a major driver in the disentanglement of nature’s mysteries. Mainly supported by technological advances such as next-generation sequencing or single-cell technologies, we now can describe the distinct cellular populations within a tissue or collection of cells in intricate detail. This allows us to understand health and disease, and it often proves instrumental in our ability to develop effective treatments. However, our current technologies are mostly geared toward an understanding of current cellular states. While various technologies can trace the lineage of cells, even the combination with global cellular state readouts does not offer accurate insights into past cellular history. Moreover, current approaches that aim to combine a past transcriptional event with such tracing can only report the historic expression of one or few genes. However, this single moment in time may have comprised many critical developmental or adaptive ‘decisions’ or ‘inputs’ that shape the current function or even location of a cell. Thus, a global recording of a transcriptional state would support a more comprehensive picture of a cell’s history. This proposal’s aim is to provide such a genome-wide record of transcription by building on recently developed technological concepts. For this, we will develop the novel approach of transcriptional endpoint marking (TEM); this technology will introduce a permanent genetic mark at the locus of actively transcribed genes. Expressing the ‘marker’ construct transiently, will inscribe a ‘snapshot’ record of the transcriptomic profile that can later be assessed by targeted genome-wide retrieval of the genomic ‘marks’. Our proposed work will provide proof-of-concept and focus on the development of a genetic toolkit that enables this analysis. In addition, it will provide a computational basis for both the data processing and