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阿尔茨海默病中启动子反义RNA的重编程m6A甲基化在三维核小体中调节全局基因转录。

Rewired m6A methylation of promoter antisense RNAs in Alzheimer's disease regulates global gene transcription in the 3D nucleome.

作者信息

Hu Benxia, Shi Yuqiang, Xiong Feng, Chen Yi-Ting, Zhu Xiaoyu, Carrillo Elisa, Wen Xingzhao, Drolet Nathan, Rajpurohit Chetan, Xu Xiangmin, Lee Dung-Fang, Soto Claudio, Zhong Sheng, Jayaraman Vasanthi, Zheng Hui, Li Wenbo

机构信息

Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.

The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.

出版信息

bioRxiv. 2025 Mar 24:2025.03.22.644756. doi: 10.1101/2025.03.22.644756.

Abstract

N-methyladenosine (m6A) is the most prevalent internal RNA modification that can impact mRNA expression post-transcriptionally. Recent progress indicates that m6A also acts on nuclear or chromatin-associated RNAs to impact transcriptional and epigenetic processes. However, the landscapes and functional roles of m6A in human brains and neurodegenerative diseases, including Alzheimer's disease (AD), have been under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex tissues of post-mortem human brains from individuals with AD and age-matched counterparts. Our results revealed AD-associated alteration of m6A methylation on both mRNAs and various noncoding RNAs. Notably, a series of promoter antisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to the locus that encodes the Tau protein. We found that is enriched in neurons, and m6A positively controls its expression. In iPSC-derived human excitatory neurons, promotes expression of hundreds of genes related to neuronal and synaptic functions, including a key AD resilience gene , and plays a neuroprotective role against excitotoxicity. By examining RNA-DNA interactome in the three-dimensional (3D) nuclei of human brains, we demonstrated that brain paRNAs can interact with both - and -chromosomal target genes to impact their transcription. These data together reveal previously unexplored landscapes and functions of noncoding RNAs and m6A methylome in brain gene regulation, neuronal survival and AD pathogenesis.

摘要

N-甲基腺苷(m6A)是最普遍的内部RNA修饰,可在转录后影响mRNA表达。最近的进展表明,m6A也作用于核RNA或与染色质相关的RNA,以影响转录和表观遗传过程。然而,m6A在人类大脑和神经退行性疾病(包括阿尔茨海默病(AD))中的图谱和功能作用尚未得到充分探索。在这里,我们使用全RNA测序和甲基化RNA免疫沉淀测序(meRIP-seq)检测了来自AD患者和年龄匹配对照的死后人类大脑中额叶皮质组织的RNA m6A甲基化组。我们的结果揭示了mRNA和各种非编码RNA上与AD相关的m6A甲基化改变。值得注意的是,一系列启动子反义RNA(paRNAs)在AD中表现出细胞类型特异性表达和变化,包括一个在编码Tau蛋白的基因座附近产生的反义RNA。我们发现该反义RNA在神经元中富集,m6A正向调控其表达。在诱导多能干细胞(iPSC)衍生的人类兴奋性神经元中,该反义RNA促进数百个与神经元和突触功能相关的基因表达,包括一个关键的AD抵抗基因,并对兴奋性毒性发挥神经保护作用。通过检测人类大脑三维(3D)细胞核中的RNA-DNA相互作用组,我们证明大脑paRNAs可以与α-和β-染色体靶基因相互作用,从而影响它们的转录。这些数据共同揭示了非编码RNA和m6A甲基化组在大脑基因调控、神经元存活和AD发病机制中以前未被探索的图谱和功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bab/11974732/705ff8947d43/nihpp-2025.03.22.644756v2-f0001.jpg

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