In the fields of synthetic biology and cell therapy, precise control of gene expression in response to specific cellular states is crucial for both functional studies and therapeutic applications. However, designing synthetic promoters with high cell-state specificity remains challenging, particularly for complex states such as T cell exhaustion.

Recently, Xie Zhen's team from Tsinghua University published a research article titled "SPECIFIC: A systematic framework for engineering cell state-responsive synthetic promoters reveals key regulators of T cell exhaustion" in Quantitative Biology, proposing an integrated framework combining chromatin accessibility analysis and machine learning for rational design of synthetic promoters.

As illustrated in Figure 1, the team developed the SPECIFIC (Synthetic Promoter Engineering for Cellular State Identification and Functional Analysis) framework, which systematically designs and validates cell state-specific synthetic promoters by integrating chromatin accessibility profiling, computational motif analysis, and synthetic biology approaches. Using T cell exhaustion as a model, the study identified 56 conserved transcription factor binding motifs associated with exhaustion by comparing exhausted T cells from mouse OT-I and human CAR-T models. Based on these motifs, the team engineered synthetic promoters and constructed gene circuits capable of sensing and responding to T cell dysfunction.

The SPECIFIC framework not only provides new tools for studying T cell exhaustion but also establishes a generalizable approach for engineering cell state-responsive synthetic promoters. The team plans to further optimize promoter specificity and explore applications in diverse cell types and therapeutic contexts.
DOI: 10.1002/qub2.97