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

Author

Listed:
  • Benxia Hu

    (University of Texas Health Science Center)

  • Yuqiang Shi

    (University of Texas Health Science Center)

  • Feng Xiong

    (University of Texas Health Science Center)

  • Yi-Ting Chen

    (University of Texas Health Science Center
    The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences)

  • Xiaoyu Zhu

    (University of Texas Health Science Center)

  • Elisa Carrillo

    (University of Texas Health Science Center)

  • Xingzhao Wen

    (University of California San Diego)

  • Nathan Drolet

    (University of Texas Health Science Center)

  • Chetan Singh Rajpurohit

    (Baylor College of Medicine)

  • Xiangmin Xu

    (University of California
    University of California)

  • Dung-Fang Lee

    (The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas Health Science Center at Houston)

  • Claudio Soto

    (The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences
    University of Texas Health Science Center)

  • Sheng Zhong

    (University of California San Diego
    University of California San Diego)

  • Vasanthi Jayaraman

    (University of Texas Health Science Center
    The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences)

  • Hui Zheng

    (Baylor College of Medicine)

  • Wenbo Li

    (University of Texas Health Science Center
    The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences)

Abstract

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.

Suggested Citation

  • 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 & , 2025. "Rewired m6A of promoter antisense RNAs in Alzheimer’s disease regulates neuronal genes in 3D nucleome," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60378-0
    DOI: 10.1038/s41467-025-60378-0
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