Morse Kaitlin, Bishop Alena L, Swerdlow Sarah, Leslie Jessica M, Ünal Elçin
Department of Molecular and Cell Biology, University of California, Berkeley, Barker Hall, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Barker Hall, Berkeley, CA 94720, USA.
Mol Cell. 2024 Aug 22;84(16):3080-3097.e9. doi: 10.1016/j.molcel.2024.06.029. Epub 2024 Jul 22.
Alternative transcription start sites can affect transcript isoform diversity and translation levels. In a recently described form of gene regulation, coordinated transcriptional and translational interference results in transcript isoform-dependent changes in protein expression. Specifically, a long undecoded transcript isoform (LUTI) is transcribed from a gene-distal promoter, interfering with expression of the gene-proximal promoter. Although 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 functional genomics, we uncovered that the Swi/Snf chromatin remodeling complex is required for co-transcriptional nucleosome remodeling that leads to LUTI-based repression. We identified genes with tandem promoters that rely on Swi/Snf function for transcriptional interference during protein folding stress, including LUTI-regulated genes. This study provides clear evidence for Swi/Snf playing a direct role in gene repression via a cis transcriptional interference mechanism.
可变转录起始位点可影响转录本异构体多样性和翻译水平。在最近描述的一种基因调控形式中，协调的转录和翻译干扰导致蛋白质表达发生转录本异构体依赖性变化。具体而言，一个长的未解码转录本异构体（LUTI）从基因远端启动子转录而来，干扰基因近端启动子的表达。尽管与LUTI表达相关的转录和染色质特征已被描述，但基于LUTI的转录干扰的潜在机制尚不清楚。通过一种无偏向的遗传方法，随后进行功能基因组学研究，我们发现Swi/Snf染色质重塑复合体是共转录核小体重塑所必需的，而这种重塑会导致基于LUTI的基因抑制。我们鉴定出具有串联启动子的基因，这些基因在蛋白质折叠应激期间依赖Swi/Snf功能进行转录干扰，包括LUTI调控的基因。这项研究为Swi/Snf通过顺式转录干扰机制在基因抑制中发挥直接作用提供了明确证据。
