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

  • Nat Commun. 2025 Jun 6;16(1):5251. doi: 10.1038/s41467-025-60378-0.
Benxia Hu  #  1 ,  Yuqiang Shi  #  1 ,  Feng Xiong  1 ,  Yi-Ting Chen  1  2 ,  Xiaoyu Zhu  1 ,  Elisa Carrillo  1 ,  Xingzhao Wen  3 ,  Nathan Drolet  1 ,  Chetan Singh Rajpurohit  4 ,  Xiangmin Xu  5  6 ,  Dung-Fang Lee  2  7 ,  Claudio Soto  2  8 ,  Sheng Zhong  3  9 ,  Vasanthi Jayaraman  1  2 ,  Hui Zheng  4 ,  Wenbo Li  10  11
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
  • 2. The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 3. Program in Bioinformatics and Systems Biology, University of California San Diego, La Jolla, CA, USA.
  • 4. Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
  • 5. Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, USA.
  • 6. Center for Neural Circuit Mapping, University of California, Irvine, CA, USA.
  • 7. Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 8. Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
  • 9. Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
  • 10. Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. [email protected].
  • 11. The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 40480976 DOI: 10.1038/s41467-025-60378-0
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.

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