小柯机器人

德国弗莱堡大学Valérie Hilgers课题组发现，转录起始位点驱动mRNA亚型的选择。2023年5月12日，《细胞》杂志在线发表了这项成果。

研究人员评估了转录起始、可变剪接和3′端部位选择之间的调节关系。应用长读测序技术，即使是最长的转录本也能从头到尾准确表示，研究人员对果蝇组织中的mRNA亚型进行量化，包括转录复杂的神经系统。研究人员发现，在果蝇的头部以及人类的大脑器官中，3′端点的选择受到转录起始位点（TSS）的全面影响。以特定的表观遗传学特征（包括p300/CBP结合）为特征的“优势启动子”，施加了一个转录约束来定义剪接和多腺苷酸化变体。优势启动子的体内缺失或过量表达以及p300/CBP的缺失破坏了3′端表达格局。这项研究表明，TSS的选择对转录本的多样性和组织特性的调控有着至关重要的影响。

据介绍，通过可变RNA加工产生不同的信使RNA亚型可以调节基因的表达和功能，这通常是以细胞类型特异性的方式。

附：英文原文

Title: Sites of transcription initiation drive mRNA isoform selection

Author: Carlos Alfonso-Gonzalez, Ivano Legnini, Sarah Holec, Laura Arrigoni, Hasan Can Ozbulut, Fernando Mateos, David Koppstein, Agnieszka Rybak-Wolf, Ulrike Bnisch, Nikolaus Rajewsky, Valérie Hilgers

Issue&Volume: 2023-05-12

Abstract: The generation of distinct messenger RNA isoforms through alternative RNA processing modulates the expression and function of genes, often in a cell-type-specific manner. Here, we assess the regulatory relationships between transcription initiation, alternative splicing, and 3′ end site selection. Applying long-read sequencing to accurately represent even the longest transcripts from end to end, we quantify mRNA isoforms in Drosophila tissues, including the transcriptionally complex nervous system. We find that in Drosophila heads, as well as in human cerebral organoids, 3′ end site choice is globally influenced by the site of transcription initiation (TSS). “Dominant promoters,” characterized by specific epigenetic signatures including p300/CBP binding, impose a transcriptional constraint to define splice and polyadenylation variants. In vivo deletion or overexpression of dominant promoters as well as p300/CBP loss disrupted the 3′ end expression landscape. Our study demonstrates the crucial impact of TSS choice on the regulation of transcript diversity and tissue identity.

DOI: 10.1016/j.cell.2023.04.012

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00408-7