Wei Guifeng, Brockdorff Neil, Zhang Tianyi
Development Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Lymphocyte Development and Single Molecule Imaging, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
iScience. 2020 Oct 29;23(11):101741. doi: 10.1016/j.isci.2020.101741. eCollection 2020 Nov 20.
Transcriptional fidelity depends on accurate promoter selection and initiation from the correct sites. In yeast, H3K36me3-mediated recruitment of the Rpd3S HDAC complex to gene bodies suppresses spurious transcription initiation. Here we describe an equivalent pathway in metazoans. PWWP2A/B is an H3K36me3 reader that forms a stable complex with HDAC1/2. We used CAGE-seq to profile all transcription initiation sites in wild-type mESCs and cells lacking PWWP2A/B. Loss of PWWP2A/B enhances spurious initiation from intragenic sites present in wild-type mESCs, and this effect is associated with increased levels of initiating Pol-II and histone acetylation. Spurious initiation events in DKO mESCs do not overlap in genomic location or chromatin features with spurious sites that arise in KO mESCs, previously reported to function in the suppression of intragenic transcriptional initiation, suggesting these pathways function cooperatively in maintaining the fidelity of transcription initiation in metazoans.
转录保真度取决于准确的启动子选择以及从正确位点起始转录。在酵母中，H3K36me3介导Rpd3S HDAC复合物募集至基因体，从而抑制错误的转录起始。在此，我们描述了后生动物中的一条等效途径。PWWP2A/B是一种H3K36me3识别蛋白，它与HDAC1/2形成稳定复合物。我们使用CAGE-seq技术对野生型小鼠胚胎干细胞（mESCs）以及缺乏PWWP2A/B的细胞中的所有转录起始位点进行了分析。PWWP2A/B的缺失增强了野生型mESCs中基因内位点的错误起始，且这种效应与起始Pol-II水平和组蛋白乙酰化水平的升高有关。双敲除（DKO）mESCs中的错误起始事件在基因组位置或染色质特征上与敲除（KO）mESCs中出现的错误位点不重叠，此前报道KO mESCs中的错误位点在抑制基因内转录起始中起作用，这表明这些途径在维持后生动物转录起始保真度方面协同发挥作用。
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