Rewired m6A methylation of promoter antisense RNAs in Alzheimer's disease regulates global gene transcription in the 3D nucleome

  • bioRxiv. 2025 Mar 24:2025.03.22.644756. doi: 10.1101/2025.03.22.644756.
Benxia Hu  1 ,  Yuqiang Shi  1 ,  Feng Xiong  1 ,  Yi-Ting Chen  1  2 ,  Xiaoyu Zhu  1 ,  Elisa Carrillo  1 ,  Xingzhao Wen  3  4 ,  Nathan Drolet  1 ,  Chetan Rajpurohit  5 ,  Xiangmin Xu  6  7 ,  Dung-Fang Lee  2  8 ,  Claudio Soto  2  9 ,  Sheng Zhong  3  4 ,  Vasanthi Jayaraman  1  2 ,  Hui Zheng  5 ,  Wenbo Li  1  2
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. Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
  • 5. Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.
  • 6. Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, USA.
  • 7. Center for Neural Circuit Mapping (CNCM), University of California, Irvine, CA, USA.
  • 8. Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 9. Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
PMID: 40196645 DOI: 10.1101/2025.03.22.644756
Abstract

N6-methyladenosine (m6A) is the most prevalent internal RNA modification that can impact mRNA expression post-transcriptionally. Recent progress indicates that m6A also acts on nuclear or chromatin-associated RNAs to impact transcriptional and epigenetic processes. However, the landscapes and functional roles of m6A in human brains and neurodegenerative diseases, including Alzheimer's disease (AD), have been under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex tissues of post-mortem human brains from individuals with AD and age-matched counterparts. Our results revealed AD-associated alteration of m6A methylation on both mRNAs and various noncoding RNAs. Notably, a series of promoter antisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to the MAPT locus that encodes the Tau Protein. We found that MAPT-paRNA is enriched in neurons, and m6A positively controls its expression. In iPSC-derived human excitatory neurons, MAPT-paRNA promotes expression of hundreds of genes related to neuronal and synaptic functions, including a key AD resilience gene MEF2C, and plays a neuroprotective role against excitotoxicity. By examining RNA-DNA interactome in the three-dimensional (3D) nuclei of human brains, we demonstrated that brain paRNAs can interact with both cis- and trans-chromosomal target genes to impact their transcription. These data together reveal previously unexplored landscapes and functions of noncoding RNAs and m6A methylome in brain gene regulation, neuronal survival and AD pathogenesis.

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