Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq

• 全文链接

使用 scTF-seq 剖析转录因子剂量对细胞重编程异质性的影响

关键词：

来源：

Nature Genetics volume

全文链接：

//agri.nais.net.cn/topic/downloadFile/434832e4-48d0-4688-a8dc-0e9781998025

来源地址：

https://www.nature.com/articles/s41588-025-02343-7

资源所属：

马铃薯基因组设计育种

类型：

学术文献

语种：

英语

原文发布日期：

2025-10-03

摘要：

Reprogramming often yields heterogeneous cell fates, yet the underlying mechanisms remain poorly understood. To address this, we developed single-cell transcription factor sequencing (scTF-seq), a single-cell technique that induces barcoded, doxycycline-inducible TF overexpression and quantifies TF dose-dependent transcriptomic changes. Applied to mouse embryonic multipotent stromal cells, scTF-seq generated a gain-of-function atlas for 384 mouse TFs, identifying key regulators of lineage specification, cell cycle control and their interplay. Leveraging single-cell resolution, we uncovered how TF dose shapes reprogramming heterogeneity, revealing both dose-dependent and stochastic cell state transitions. We classified TFs into low-capacity and high-capacity groups, with the latter further subdivided by dose sensitivity. Combinatorial scTF-seq demonstrated that TF interactions can shift from synergistic to antagonistic depending on the relative dose. Altogether, scTF-seq enables the dissection of TF function, dose and cell fate control, providing a high-resolution framework to understand and predict reprogramming outcomes, advancing gene regulation research and the design of cell engineering strategies.