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

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 and Wenbo Li ()
Additional contact information
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
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
Dung-Fang Lee: The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences
Claudio Soto: The University of Texas MD Anderson Cancer Center and UTHealth Houston Graduate School of Biomedical Sciences
Sheng Zhong: University of California San Diego
Vasanthi Jayaraman: University of Texas Health Science Center
Hui Zheng: Baylor College of Medicine
Wenbo Li: University of Texas Health Science Center

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60378-0

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