2026年8月19日，美国斯坦福大学Theodore L. Roth等合作在《细胞》上发表研究，开发了一种名为DESynR（结构域工程化合成与重组）的进化引导方法，通过重组天然转录因子的结构域设计出合成转录因子，其中DESynR AP-1转录因子在体内外抗肿瘤实验中均显著优于天然AP-1转录因子，并能诱导T细胞发生广泛的转录和表观遗传重编程。
人类蛋白编码基因是通过祖先基因的结构域重排进化而来的。研究人员开发了一种可扩展的、进化引导的方法，用于从蛋白质家族内的组成结构域组装新基因，称为DESynR（结构域工程化合成与重组）基因。在原代人T细胞中，DESynR激活蛋白-1（AP-1）转录因子（TFs）在体外和体内抗肿瘤实验中均显著优于天然AP-1 TF。DESynR AP-1 TF可诱导广泛的转录和表观遗传重编程，并建立非天然的T细胞状态，优化了耗竭、效应功能和细胞毒性功能以及持久性等特征——有时还会利用来自不同细胞类型的基因模块。这种重编程主要由已确定的AP-1结合调控元件的差异调控驱动，而非通过独特的结合实现。最后，研究人员筛选了DESynR ETS（ erythroblast transformation-specific）和FOX（forkhead box）家族的TF，以验证该方法在不同蛋白质家族中的普适性。
总体而言，该研究表明，重构现有蛋白质结构域可能会发现非进化基因，这些基因能够编程具有治疗相关性的细胞状态。
附：英文原文
Title: Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function
Author: Oliver Takacsi-Nagy, Sivakanthan Kasinathan, Austin Hartman, Yajie Yin, Lujing Wu, Andy Y. Chen, Laura M. Moser, Audre P. May, Gabriella C. Reeder, Emily Celallos Fuentes, Courtney Kernick, Johnathan Lu, Alison K. McClellan, Colin J. Raposo, Brendan Terrall, Nicole E. Theberath, Patrick K. Yan, Peng Xu, Elena Sotillo, Justin Eyquem, Crystal L. Mackall, Theodore L. Roth, Ansuman T. Satpathy
Issue&Volume: 2026-08-19
Abstract: Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence—sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.
DOI: 10.1016/j.cell.2026.07.054
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00923-2