澳大利亚墨尔本大学Mark A. Dawson、Charles C. Bell研究组通过辅助因子比较筛选，揭示了转录激活结构域和核心启动子对转录机制的影响。2024年5月20日出版的《自然—遗传学》杂志发表了这项成果。

研究人员将GAL4转活化测定与CRISPR-Cas9比较筛选相结合，鉴定了人体细胞中九种不同的转录因子（TF）和核心启动子所使用的辅助因子。利用这个数据集，研究人员将TF与辅助因子联系起来，并把辅助因子分为普遍存在和特异的，并发现了转录的共同依赖性。通过还原、比较的方法，研究证明了TFs并不显示离散的激活机制。相反，每种TF都依赖于独特的辅助因子组合，从而影响转录的不同步骤。

相比之下，核心启动子的影响似乎相对离散。不同类别的启动子受到启动或暂停释放的限制，这影响了它们的动态范围以及与辅助因子的兼容性。总之，该辅助因子比较筛选描述了转录因子、辅助因子和核心启动子之间的相互作用，确定了它们影响转录的一般机制。

据介绍，真核生物TF通过在启动子区招募辅助因子来激活基因表达。然而，人们对转录因子、启动子及其相关辅助因子之间的关系仍然知之甚少。

附：英文原文

Title: Comparative cofactor screens show the influence of transactivation domains and core promoters on the mechanisms of transcription

Author: Bell, Charles C., Balic, Jesse J., Talarmain, Laure, Gillespie, Andrea, Scolamiero, Laura, Lam, Enid Y. N., Ang, Ching-Seng, Faulkner, Geoffrey J., Gilan, Omer, Dawson, Mark A.

Issue&Volume: 2024-05-20

Abstract: Eukaryotic transcription factors (TFs) activate gene expression by recruiting cofactors to promoters. However, the relationships between TFs, promoters and their associated cofactors remain poorly understood. Here we combine GAL4-transactivation assays with comparative CRISPR–Cas9 screens to identify the cofactors used by nine different TFs and core promoters in human cells. Using this dataset, we associate TFs with cofactors, classify cofactors as ubiquitous or specific and discover transcriptional co-dependencies. Through a reductionistic, comparative approach, we demonstrate that TFs do not display discrete mechanisms of activation. Instead, each TF depends on a unique combination of cofactors, which influences distinct steps in transcription. By contrast, the influence of core promoters appears relatively discrete. Different promoter classes are constrained by either initiation or pause-release, which influences their dynamic range and compatibility with cofactors. Overall, our comparative cofactor screens characterize the interplay between TFs, cofactors and core promoters, identifying general principles by which they influence transcription.

DOI: 10.1038/s41588-024-01749-z

Source: https://www.nature.com/articles/s41588-024-01749-z