Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Institute for Virology and Immunobiology, University of Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany.
Mol Cell. 2021 Aug 5;81(15):3110-3127.e14. doi: 10.1016/j.molcel.2021.06.016. Epub 2021 Jul 6.
SPT6 is a histone chaperone that tightly binds RNA polymerase II (RNAPII) during transcription elongation. However, its primary role in transcription is uncertain. We used targeted protein degradation to rapidly deplete SPT6 in human cells and analyzed defects in RNAPII behavior by a multi-omics approach and mathematical modeling. Our data indicate that SPT6 is a crucial factor for RNAPII processivity and is therefore required for the productive transcription of protein-coding genes. Unexpectedly, SPT6 also has a vital role in RNAPII termination, as acute depletion induced readthrough transcription for thousands of genes. Long-term depletion of SPT6 induced cryptic intragenic transcription, as observed earlier in yeast. However, this phenotype was not observed upon acute SPT6 depletion and therefore can be attributed to accumulated epigenetic perturbations in the prolonged absence of SPT6. In conclusion, targeted degradation of SPT6 allowed the temporal discrimination of its function as an epigenetic safeguard and RNAPII elongation factor.
SPT6 是一种组蛋白伴侣，在转录延伸过程中与 RNA 聚合酶 II（RNAPII）紧密结合。然而，其在转录中的主要作用尚不确定。我们使用靶向蛋白降解技术在人细胞中快速耗尽 SPT6，并通过多组学方法和数学建模分析 RNAPII 行为的缺陷。我们的数据表明，SPT6 是 RNAPII 延伸性的关键因素，因此是编码蛋白基因有效转录所必需的。出乎意料的是，SPT6 在 RNAPII 终止中也起着至关重要的作用，因为急性耗尽会导致数千个基因的通读转录。长期耗尽 SPT6 会诱导基因内隐匿转录，这在酵母中更早被观察到。然而，在急性 SPT6 耗尽时并未观察到这种表型，因此可以归因于在 SPT6 长期缺失时积累的表观遗传扰动。总之，靶向降解 SPT6 允许在时间上区分其作为表观遗传保护因子和 RNAPII 延伸因子的功能。
