小柯机器人

5-羟甲基胞嘧啶可阻止引起先天免疫反应的异常转录本生成
2022-12-22 20:47

德国马克斯普朗克心肺研究所Thomas Braun和Xuejun Yuan共同合作,近期取得重要工作进展,他们研究发现5-羟甲基胞嘧啶可阻止引起先天免疫反应的异常转录本生成。相关研究成果2022年12月20日在线发表于《自然—遗传学》杂志上。

据介绍,功能性转录物的产生需要在规则的起始位点进行转录起始,避免产生潜在危险的异常RNA。维持转录本保真度的机制以及异常转录物对细胞生理和器官功能的影响,目前还不清楚。

研究人员发现,TET3可以将5-甲基胞嘧啶依次氧化为5-羟甲基胞嘧啶(5hmC)和其它衍生物,阻止RNA聚合酶 II pSer5异常地进入气道平滑肌细胞的高表达基因,从而确保在标准起始位点的忠实转录起始。SMC中TET3依赖性5hmC产生的缺失导致异常转录物的积累,积累得异常转录物刺激核内体核酸传感TLR7/8信号通路,从而引发类似于人类支气管哮喘的大规模炎症和气道重塑。

此外,研究人员发现与对照样本相比,人类哮喘气道中的5hmC水平显著更低。抑制异常转录物生成,可能对预防哮喘慢性炎症有重要意义。

附:英文原文

Title: Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine

Author: Wu, Fan, Li, Xiang, Looso, Mario, Liu, Hang, Ding, Dong, Gnther, Stefan, Kuenne, Carsten, Liu, Shuya, Weissmann, Norbert, Boettger, Thomas, Atzberger, Ann, Kolahian, Saeed, Renz, Harald, Offermanns, Stefan, Grtner, Ulrich, Potente, Michael, Zhou, Yonggang, Yuan, Xuejun, Braun, Thomas

Issue&Volume: 2022-12-20

Abstract: Generation of functional transcripts requires transcriptional initiation at regular start sites, avoiding production of aberrant and potentially hazardous aberrant RNAs. The mechanisms maintaining transcriptional fidelity and the impact of spurious transcripts on cellular physiology and organ function have not been fully elucidated. Here we show that TET3, which successively oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other derivatives, prevents aberrant intragenic entry of RNA polymeraseII pSer5 into highly expressed genes of airway smooth muscle cells, assuring faithful transcriptional initiation at canonical start sites. Loss of TET3-dependent 5hmC production in SMCs results in accumulation of spurious transcripts, which stimulate the endosomal nucleic-acid-sensing TLR7/8 signaling pathway, thereby provoking massive inflammation and airway remodeling resembling human bronchial asthma. Furthermore, we found that 5hmC levels are substantially lower in human asthma airways compared with control samples. Suppression of spurious transcription might be important to prevent chronic inflammation in asthma.

DOI: 10.1038/s41588-022-01252-3

Source: https://www.nature.com/articles/s41588-022-01252-3

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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