Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models.
Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models.
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DOI：
10.1038/s41467-023-37339-6
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发表时间：
2023-04-05
影响因子：
16.6
通讯作者：
Ellis, James
中科院分区：
文献类型：
--
作者：
Rodrigues, Deivid C.;Mufteev, Marat;Yuki, Kyoko E.;Narula, Ashrut;Wei, Wei;Piekna, Alina;Liu, Jiajie;Pasceri, Peter;Rissland, Olivia S.;Wilson, Michael D.;Ellis, James
Rett 综合征 (RTT) 的转录变化被认为与稳态 mRNA 水平直接相关，但小鼠中有限的证据表明转录变化可以通过转录后调节来补偿。我们使用 RATEseq 测量 RTT 患者神经元的转录率和 mRNA 半衰期变化，并重新解释 Mecp2 小鼠的核和全细胞 RNAseq。基因通过改变转录率或半衰期而失调，并且当两者都改变时得到缓冲。我们利用分类器模型来预测转录率变化的方向，并发现三个二核苷酸的组合频率是比 CA 和 CG 更好的预测因子。 MicroRNA 和 RNA 结合蛋白 (RBP) 基序富集在具有半衰期变化的基因 3ʹUTR 中。核 RBP 基序在缓冲基因上富集，转录率增加。我们确定了人类和小鼠的转录后机制，当转录调节基因在神经发育障碍中发生突变时，这些机制会改变半衰期或缓冲转录率的变化。 Rett 综合征 (RTT) 是一种由转录调节因子 MECP2 突变引起的神经发育障碍。在这里，作者测量了 RTT 患者来源的神经元中的转录率和 mRNA 半衰期变化，以显示 mRNA 半衰期变化缓冲的转录率。
Transcriptional changes in Rett syndrome (RTT) are assumed to directly correlate with steady-state mRNA levels, but limited evidence in mice suggests that changes in transcription can be compensated by post-transcriptional regulation. We measure transcription rate and mRNA half-life changes in RTT patient neurons using RATEseq, and re-interpret nuclear and whole-cell RNAseq from Mecp2 mice. Genes are dysregulated by changing transcription rate or half-life and are buffered when both change. We utilized classifier models to predict the direction of transcription rate changes and find that combined frequencies of three dinucleotides are better predictors than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs are enriched in 3ʹUTRs of genes with half-life changes. Nuclear RBP motifs are enriched on buffered genes with increased transcription rate. We identify post-transcriptional mechanisms in humans and mice that alter half-life or buffer transcription rate changes when a transcriptional modulator gene is mutated in a neurodevelopmental disorder. Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.
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影响因子：
25
作者：
Guo, Junjie U.;Su, Yijing;Shin, Joo Heon;Shin, Jaehoon;Li, Hongda;Xie, Bin;Zhong, Chun;Hu, Shaohui;Le, Thuc;Fan, Guoping;Zhu, Heng;Chang, Qiang;Gao, Yuan;Ming, Guo-li;Song, Hongjun
通讯作者：
Song, Hongjun
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3.5
作者：
Ben-Shachar S;Chahrour M;Thaller C;Shaw CA;Zoghbi HY
通讯作者：
Zoghbi HY
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8.8
作者：
Agarwal, Vikram;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
11.8
作者：
Cheng, Tian-Lin;Wang, Zhizhi;Qiu, Zilong
通讯作者：
Qiu, Zilong
影响因子：
56.9
作者：
Ibrahim, Abdulkhaleg;Papin, Christophe;Hamiche, Ali
通讯作者：
Hamiche, Ali