The fidelity of transcription in human cells.
The fidelity of transcription in human cells.
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DOI：
10.1073/pnas.2210038120
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发表时间：
2023-01-31
影响因子：
11.1
通讯作者：
Vermulst, Marc
中科院分区：
文献类型：
--
作者：
Chung, Claire;Verheijen, Bert M.;Zhang, Xinmin;Huang, Biao;Coakley, Aeowynn;McGann, Eric;Wade, Emily;Dinep-Schneider, Olivia;LaGosh, Jessica;Anagnostou, Maria-Eleni;Simpson, Stephen;Thomas, Kelly;Ernst, Mimi;Rattray, Allison;Lynch, Michael;Kashlev, Mikhail;Benayoun, Berenice A.;Li, Zhongwei;Strathern, Jeffrey;Gout, Jean-Francois;Vermulst, Marc
准确的转录是忠实表达遗传信息所必需的。为了确定控制转录保真度的分子机制，我们监测了人类胚胎干细胞的转录突变。这些测量提供了人类细胞中转录保真度的第一个严格估计，并确定了调节错误率的多种遗传和表观遗传因素。此外，我们开发了一种新的报告小鼠，表明神经元，包括海马神经元，对转录突变高度敏感，为转录错误在包括阿尔茨海默病在内的各种神经系统疾病中发挥作用的假设提供了新的支持。这些实验为基因表达的保真度和支撑生命中心法则的分子机制提供了前所未有的见解。为了确定人类细胞中的转录错误率，我们使用循环测序方法分析了H1人类胚胎干细胞的转录组，该方法允许对转录组进行高保真度测序。这些实验确定了分布在人类细胞中每一种主要RNA物种中的大约10万个错误。我们的研究结果表明，不同的RNA种类显示出不同的错误率，这表明人类细胞优先考虑一些RNA的保真度。我们将检测到的错误率与人类基因组的各种遗传和表观遗传特征进行交叉比对，发现人类细胞的体内错误率沿着转录物的长度变化，并受到遗传背景、重复元件、表观遗传标记和转录速度的进一步修饰。我们的实验进一步表明，BRCA1，一种与乳腺癌有关的DNA修复蛋白，在抑制转录错误中具有先前未知的作用。最后，我们分析了转录错误在一个新的小鼠模型的多个组织中的分布，发现与其他细胞类型相比，它们优先发生在神经元中。这些观察结果进一步支持了转录错误在包括阿尔茨海默病在内的各种神经系统疾病的进展中起关键作用的观点。
Accurate transcription is required for the faithful expression of genetic information. To identify molecular mechanisms that control the fidelity of transcription, we monitored transcriptional mutagenesis in human embryonic stem cells. These measurements provide the first rigorous estimate of the fidelity of transcription in human cells and identify multiple genetic and epigenetic factors that modulate the error rate. In addition, we developed a new reporter mouse that suggests that neurons, including hippocampal neurons, are highly sensitive to transcriptional mutagenesis, lending new support to the hypothesis that transcription errors play a role in various neurological disorders, including Alzheimer’s disease. These experiments provide unprecedented insights into the fidelity of gene expression and the molecular mechanisms that underpin the central dogma of life. To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others. Cross-referencing the errors that we detected with various genetic and epigenetic features of the human genome revealed that the in vivo error rate in human cells changes along the length of a transcript and is further modified by genetic context, repetitive elements, epigenetic markers, and the speed of transcription. Our experiments further suggest that BRCA1, a DNA repair protein implicated in breast cancer, has a previously unknown role in the suppression of transcription errors. Finally, we analyzed the distribution of transcription errors in multiple tissues of a new mouse model and found that they occur preferentially in neurons, compared to other cell types. These observations lend additional weight to the idea that transcription errors play a key role in the progression of various neurological disorders, including Alzheimer’s disease.
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DOI：
10.1073/pnas.2004077118
发表时间：
2021-01-05
影响因子：
11.1
作者：
Fritsch, C.;Gout, J-F;Vermulst, M.
通讯作者：
Vermulst, M.
影响因子：
1.2
作者：
Fritsch, Clark;Gout, Jean-Francois Pierre;Vermulst, Marc
通讯作者：
Vermulst, Marc
DOI：
10.1073/pnas.0912451107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Loh, Ern;Salk, Jesse J.;Loeb, Lawrence A.
通讯作者：
Loeb, Lawrence A.
影响因子：
16.6
作者：
Eggington, Julie M.;Greene, Tom;Bass, Brenda L.
通讯作者：
Bass, Brenda L.
影响因子：
16
作者：
Brégeon, D;Doddridge, ZA;Doetsch, PW
通讯作者：
Doetsch, PW