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Evolutionarily guided transcription factor design programs novel T cell states

Takacsi-Nagy, O.; Hartman, A.; Chen, A. Y.; Yin, Y.; Reeder, G. C.; Kernick, C.; Lu, J.; McClellan, A. K.; Raposo, C. J.; Theberath, N. E.; Yan, P. K.; Eyquem, J.; Roth, T. L.; Satpathy, A. T.

2024-11-08 genetics
10.1101/2024.11.06.622344 bioRxiv
Show abstract

Protein-coding genes in the human genome evolved via modular rearrangement of domains from ancestral genes1. Here, we develop a scalable, evolutionarily guided method to assemble novel protein-coding genes from constituent domains within a protein family, termed DESynR (Domain Engineered via Synthesis and Recombination) genes. Using primary human chimeric antigen receptor T cells as a model system, we find that the expression of DESynR Activator Protein-1 (AP-1) transcription factors (TFs) significantly outperforms the overexpression of natural AP-1 TFs in multiple functional assays in vitro and in vivo. Top DESynR AP-1 TFs exhibit non-intuitive architectures of constituent domains, including from TFs that are not canonically expressed in T cells. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming of T cells and, in some cases, lead to the development of non-natural T cell states, engaging gene expression modules from disparate human cell types. Taken together, we demonstrate that novel configurations of existing protein domains may uncover non-evolved genes that program cell states with therapeutically relevant functions.

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