Regulation of transcriptional interference by the Swi/Snf complex [TL-seq]

Alternative transcription start sites regulate transcript isoform diversity and, in turn, often regulate translation levels for a given gene. Recently, a form of gene regulation was described in which transcriptional and translational interference are coordinated, resulting in transcript isoform-dependent changes in protein expression for affected genes. In this form of gene regulation, a long undecoded transcript isoform (LUTI) is transcribed from a gene-distal promoter, interfering with expression of the gene-proximal promoter. While transcriptional and chromatin features associated with LUTI expression have been described, the mechanism underlying LUTI-based transcriptional interference is not well-understood. Using an unbiased genetic approach followed by integrated genomic analysis, we have found that the Swi/Snf chromatin remodeling complex is required for co-transcriptional nucleosome remodeling that leads to LUTI-mediated repression. We uncovered twelve genes with tandem promoters that rely on Swi/Snf function for transcriptional interference during protein folding stress, including three LUTI-regulated genes. Our results provide evidence that, in addition to its canonical function in gene activation, the Swi/Snf complex directly represses promoters that are subject to transcriptional readthrough.可变转录起始位点（Alternative transcription start sites）可调控转录本异构体多样性，进而通常亦可调控特定基因的翻译水平。近期有研究报道了一类协同调控转录与翻译的基因调控模式，可使受影响基因的蛋白质表达水平随转录本异构体的差异发生改变。在该调控模式中，从基因远端启动子转录生成的长未解码转录本异构体（long undecoded transcript isoform，LUTI），会干扰基因近端启动子的基因表达。尽管已有研究阐明了与LUTI表达相关的转录与染色质特征，但基于LUTI的转录干扰机制仍未得到充分解析。本研究通过无偏遗传方法结合整合基因组分析，发现Swi/Snf染色质重塑复合物（Swi/Snf chromatin remodeling complex）是介导共转录核小体重塑的关键因子，而该重塑过程可引发LUTI介导的基因抑制。我们在蛋白质折叠应激过程中鉴定出12个依赖Swi/Snf功能实现转录干扰的串联启动子基因，其中包含3个受LUTI调控的基因。本研究结果证实，Swi/Snf复合物除了具备基因激活的经典功能外，还可直接抑制受转录通读影响的启动子活性。