Scholarlink

<p>N<sup>6</sup>-methyladenosine (m6A) is an abundant internal RNA modification that can impact gene expression at both post-transcriptional and transcriptional levels. However, the landscapes and functions of m6A in human brains and neurodegenerative diseases, including Alzheimer’s disease (AD), are under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex of post-mortem brains from individuals with or without AD, which revealed m6A alteration on both mRNAs and various noncoding RNAs. Notably, many <Emphasis Type="Underline">p</Emphasis>romoter-<Emphasis Type="Underline">a</Emphasis>ntisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to <i>MAPT</i> that encodes the Tau protein. <i>MAPT-paRNA</i> is highly expressed in neurons, and m6A positively controls its expression. In iPSC-derived human excitatory neurons, <i>MAPT-paRNA</i> does not impact the nearby <i>MAPT</i> mRNA, but instead promotes expression of hundreds of neuronal and synaptic genes, and is protective against excitotoxicity. Analysis of single nuclei RNA-DNA interactome in human brains supports that brain paRNAs interact with both <i>cis</i>- and <i>trans</i>-chromosomal target genes to impact their transcription. These data reveal landscapes and functions of noncoding RNAs and m6A in brain gene regulation and AD pathogenesis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Rewired m6A of promoter antisense RNAs in Alzheimer’s disease regulates neuronal genes in 3D nucleome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月6日

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

摘要

N6-methyladenosine (m6A) is an abundant internal RNA modification that can impact gene expression at both post-transcriptional and transcriptional levels. However, the landscapes and functions of m6A in human brains and neurodegenerative diseases, including Alzheimer’s disease (AD), are under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex of post-mortem brains from individuals with or without AD, which revealed m6A alteration on both mRNAs and various noncoding RNAs. Notably, many promoter-antisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to MAPT that encodes the Tau protein. MAPT-paRNA is highly expressed in neurons, and m6A positively controls its expression. In iPSC-derived human excitatory neurons, MAPT-paRNA does not impact the nearby MAPT mRNA, but instead promotes expression of hundreds of neuronal and synaptic genes, and is protective against excitotoxicity. Analysis of single nuclei RNA-DNA interactome in human brains supports that brain paRNAs interact with both cis- and trans-chromosomal target genes to impact their transcription. These data reveal landscapes and functions of noncoding RNAs and m6A in brain gene regulation and AD pathogenesis.