Kelbert Moran, Jordán-Pla Antonio, de Miguel-Jiménez Lola, García-Martínez José, Selitrennik Michael, Guterman Adi, Henig Noa, Granneman Sander, Pérez-Ortín José E, Chávez Sebastián, Choder Mordechai
Department of Molecular Microbiology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Instituto Biotecmed, Facultad de Biológicas, Universitat de València, Burjassot, Spain.
Elife. 2024 Oct 2;12:RP90766. doi: 10.7554/eLife.90766.
To function effectively as an integrated system, the transcriptional and post-transcriptional machineries must communicate through mechanisms that are still poorly understood. Here, we focus on the zinc-finger Sfp1, known to regulate transcription of proliferation-related genes. We show that Sfp1 can regulate transcription either by binding to promoters, like most known transcription activators, or by binding to the transcribed regions (gene bodies), probably via RNA polymerase II (Pol II). We further studied the first mode of Sfp1 activity and found that, following promoter binding, Sfp1 binds to gene bodies and affects Pol II configuration, manifested by dissociation or conformational change of its Rpb4 subunit and increased backtracking. Surprisingly, Sfp1 binds to a subset of mRNAs co-transcriptionally and stabilizes them. The interaction between Sfp1 and its client mRNAs is controlled by their respective promoters and coincides with Sfp1's dissociation from chromatin. Intriguingly, Sfp1 dissociation from the chromatin correlates with the extent of the backtracked Pol II. We propose that, following promoter recruitment, Sfp1 accompanies Pol II and regulates backtracking. The backtracked Pol II is more compatible with Sfp1's relocation to the nascent transcripts, whereupon Sfp1 accompanies these mRNAs to the cytoplasm and regulates their stability. Thus, Sfp1's co-transcriptional binding imprints the mRNA fate, serving as a paradigm for the cross-talk between the synthesis and decay of specific mRNAs, and a paradigm for the dual-role of some zinc-finger proteins. The interplay between Sfp1's two modes of transcription regulation remains to be examined.
为了作为一个整合系统有效地发挥功能，转录和转录后机制必须通过仍知之甚少的机制进行通信。在这里，我们聚焦于锌指蛋白Sfp1，已知其可调节增殖相关基因的转录。我们发现，Sfp1既可以像大多数已知的转录激活因子那样通过结合启动子来调节转录，也可能通过RNA聚合酶II（Pol II）结合到转录区域（基因体）来调节转录。我们进一步研究了Sfp1活性的第一种模式，发现启动子结合后，Sfp1结合到基因体并影响Pol II的构象，表现为其Rpb4亚基的解离或构象变化以及回溯增加。令人惊讶的是，Sfp1在转录过程中结合到一部分mRNA并使其稳定。Sfp1与其客户mRNA之间的相互作用由它们各自的启动子控制，并且与Sfp1从染色质上的解离同时发生。有趣的是，Sfp1从染色质上的解离与回溯的Pol II的程度相关。我们提出，在被招募到启动子后，Sfp1伴随Pol II并调节回溯。回溯的Pol II与Sfp1重新定位到新生转录本更兼容，随后Sfp1伴随这些mRNA进入细胞质并调节它们的稳定性。因此，Sfp1的转录过程中的结合决定了mRNA的命运，这是特定mRNA合成与降解之间相互作用的范例，也是一些锌指蛋白双重作用的范例。Sfp1两种转录调节模式之间的相互作用仍有待研究。
