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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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    1. Deepak P. Patil & Chun-Kan Chen & Brian F. Pickering & Amy Chow & Constanza Jackson & Mitchell Guttman & Samie R. Jaffrey, 2016. "m6A RNA methylation promotes XIST-mediated transcriptional repression," Nature, Nature, vol. 537(7620), pages 369-373, September.
    2. Yang Xiang & Benoit Laurent & Chih-Hung Hsu & Sigrid Nachtergaele & Zhike Lu & Wanqiang Sheng & Chuanyun Xu & Hao Chen & Jian Ouyang & Siqing Wang & Dominic Ling & Pang-Hung Hsu & Lee Zou & Ashwini Ja, 2017. "Correction: Corrigendum: RNA m6A methylation regulates the ultraviolet-induced DNA damage response," Nature, Nature, vol. 552(7685), pages 430-430, December.
    3. Yang Xiang & Benoit Laurent & Chih-Hung Hsu & Sigrid Nachtergaele & Zhike Lu & Wanqiang Sheng & Chuanyun Xu & Hao Chen & Jian Ouyang & Siqing Wang & Dominic Ling & Pang-Hung Hsu & Lee Zou & Ashwini Ja, 2017. "RNA m6A methylation regulates the ultraviolet-induced DNA damage response," Nature, Nature, vol. 543(7646), pages 573-576, March.
    4. Tomasz Chelmicki & Emeline Roger & Aurélie Teissandier & Mathilde Dura & Lorraine Bonneville & Sofia Rucli & François Dossin & Camille Fouassier & Sonia Lameiras & Deborah Bourc’his, 2021. "m6A RNA methylation regulates the fate of endogenous retroviruses," Nature, Nature, vol. 591(7849), pages 312-316, March.
    5. Roberto Simone & Faiza Javad & Warren Emmett & Oscar G. Wilkins & Filipa Lourenço Almeida & Natalia Barahona-Torres & Justyna Zareba-Paslawska & Mazdak Ehteramyan & Paola Zuccotti & Angelika Modelska , 2021. "MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration," Nature, Nature, vol. 594(7861), pages 117-123, June.
    6. Eliza Yankova & Wesley Blackaby & Mark Albertella & Justyna Rak & Etienne Braekeleer & Georgia Tsagkogeorga & Ewa S. Pilka & Demetrios Aspris & Dan Leggate & Alan G. Hendrick & Natalie A. Webster & By, 2021. "Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia," Nature, Nature, vol. 593(7860), pages 597-601, May.
    7. Xingzhao Wen & Zhifei Luo & Wenxin Zhao & Riccardo Calandrelli & Tri C. Nguyen & Xueyi Wan & John Lalith Charles Richard & Sheng Zhong, 2024. "Single-cell multiplex chromatin and RNA interactions in ageing human brain," Nature, Nature, vol. 628(8008), pages 648-656, April.
    8. An Xu & Mo Liu & Mo-Fan Huang & Yang Zhang & Ruifeng Hu & Julian A. Gingold & Ying Liu & Dandan Zhu & Chian-Shiu Chien & Wei-Chen Wang & Zian Liao & Fei Yuan & Chih-Wei Hsu & Jian Tu & Yao Yu & Taylor, 2023. "Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    9. Jiadong Liu & Mingwei Gao & Jiangping He & Kaixin Wu & Siyuan Lin & Lingmei Jin & Yaping Chen & He Liu & Junjie Shi & Xiwei Wang & Lei Chang & Yingying Lin & Yu-Li Zhao & Xiaofei Zhang & Man Zhang & G, 2021. "The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity," Nature, Nature, vol. 591(7849), pages 322-326, March.
    10. Hailing Shi & Xuliang Zhang & Yi-Lan Weng & Zongyang Lu & Yajing Liu & Zhike Lu & Jianan Li & Piliang Hao & Yu Zhang & Feng Zhang & You Wu & Jary Y. Delgado & Yijing Su & Meera J. Patel & Xiaohua Cao , 2018. "m6A facilitates hippocampus-dependent learning and memory through YTHDF1," Nature, Nature, vol. 563(7730), pages 249-253, November.
    11. Fan Yang & Bogdan Tanasa & Rudi Micheletti & Kenneth A. Ohgi & Aneel K. Aggarwal & Michael G. Rosenfeld, 2021. "Shape of promoter antisense RNAs regulates ligand-induced transcription activation," Nature, Nature, vol. 595(7867), pages 444-449, July.
    12. Sarah Djebali & Carrie A. Davis & Angelika Merkel & Alex Dobin & Timo Lassmann & Ali Mortazavi & Andrea Tanzer & Julien Lagarde & Wei Lin & Felix Schlesinger & Chenghai Xue & Georgi K. Marinov & Jaina, 2012. "Landscape of transcription in human cells," Nature, Nature, vol. 489(7414), pages 101-108, September.
    13. Wenqi Xu & Jiahui Li & Chenxi He & Jing Wen & Honghui Ma & Bowen Rong & Jianbo Diao & Liyong Wang & Jiahua Wang & Feizhen Wu & Li Tan & Yujiang Geno Shi & Yang Shi & Hongjie Shen, 2021. "METTL3 regulates heterochromatin in mouse embryonic stem cells," Nature, Nature, vol. 591(7849), pages 317-321, March.
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