Transcriptional machinery plays central roles in T cell differentiation and immune gene regulation. Major transcription factors (TFs) act as master regulators in T cell response via binding to the cis-regulatory elements (CREs) of variable downstream targets. Using in vivo CRISPR screening, we identified Fli1 as a transcriptional immune checkpoint in limiting hyper immune activation and a potential target to enhance anti-tumor effect of antigen specific T cells. By integrating deep learning, epigenetic profiling and perturbation and base editing, we found a core ~170 bps interval in the 1.5kb CRE in controlling CD69 expression, whereas a single C-to-T transition on Chr12:9764948 having the strongest effect in reducing CD69 expression via tuning GATA3/BHLHE40 DNA-binding. With all these studies, we have built systematic strategies to dissect transcriptional control during T cell response and provide solutions for screening potential drug targets or designing immune circuitries for microenvironmental specific cell therapies.
Zeyu Chen et al., Integrative dissection of gene regulatory elements at base resolution. bioRxiv, 2022
Zeyu Chen et al., In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell, 2021
Zeyu Chen et al., TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity, 2019.