Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination.
Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination.
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DOI：
10.1016/j.molcel.2021.06.016
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发表时间：
2021-08-05
期刊：
影响因子：
16
通讯作者：
Wolf E
中科院分区：
文献类型：
--
作者：
Narain A;Bhandare P;Adhikari B;Backes S;Eilers M;Dölken L;Schlosser A;Erhard F;Baluapuri A;Wolf E
SPT6是在转录延伸期间紧密结合RNA聚合酶II（RNAPII）的组蛋白伴侣。然而，它在转录中的主要作用是不确定的。我们使用靶向蛋白质降解来快速耗尽人类细胞中的SPT6，并通过多组学方法和数学建模来分析RNAPII行为中的缺陷。我们的数据表明，SPT6是RNAPII持续合成能力的关键因素，因此是蛋白质编码基因的生产性转录所必需的。出乎意料的是，SPT6在RNAPII终止中也具有至关重要的作用，因为急性消耗诱导数千个基因的通读转录。长期耗尽的SPT6诱导隐蔽的基因内转录，如早期在酵母中观察到的。然而，这种表型在急性SPT6耗竭时没有观察到，因此可以归因于在长期缺乏SPT6的情况下累积的表观遗传扰动。总之，有针对性的降解SPT6允许其作为表观遗传保护和RNAPII延伸因子的功能的时间歧视。生长素诱导的降解区分人类SPT6在转录中的直接作用SPT6的急性丢失全面损害RNAP II的持续合成能力和速度SPT6是蛋白质编码基因上有效转录终止所需的长期丢失SPT6最终导致隐蔽的基因内转录组蛋白伴侣蛋白SPT6对于在RNAP II转录后维持表观遗传完整性是必不可少的。通过多组学和数学建模研究靶向急性耗竭SPT6的影响，Narain et al.揭示了SPT6在确保人类细胞中有效转录延伸和终止中的直接作用。
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. Auxin-inducible degradation discriminates direct roles of human SPT6 in transcription Acute loss of SPT6 globally impairs RNAPII processivity and speed SPT6 is required for efficient transcription termination on protein-coding genes Long-term loss of SPT6 ultimately results in cryptic intragenic transcription Histone chaperone SPT6 is essential for maintaining epigenetic integrity in the wake of transcription by RNAP II. By studying the effects of targeted acute depletion of SPT6 with multi-omics and mathematical modeling, Narain et al. uncovered direct roles of SPT6 in ensuring efficient transcription elongation and termination in human cells.
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影响因子：
13.8
作者：
Gates LA;Foulds CE;O'Malley BW
通讯作者：
O'Malley BW
DOI：
10.1073/pnas.0807297105
发表时间：
2008-09-30
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0804424105
发表时间：
2008-06-24
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
16
作者：
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通讯作者：
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