Rewired m6A of promoter antisense RNAs in Alzheimer’s disease regulates neuronal genes in 3D nucleome
N<sup>6</sup>-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.
Authors
- Xiangmin Xu (ORCID: https://orcid.org/0000-0002-5828-1533)
- Yuqiang Shi
- Feng Xiong (ORCID: https://orcid.org/0000-0001-7051-6668)
- Chetan Singh Rajpurohit (ORCID: https://orcid.org/0000-0002-4999-155X)
- Sheng Zhong (ORCID: https://orcid.org/0000-0001-6419-7453)
- Benxia Hu
- Vasanthi Jayaraman (ORCID: https://orcid.org/0000-0002-2686-7310)
- Hui Zheng (ORCID: https://orcid.org/0000-0002-5427-3798)
- Nathan Drolet
- Xingzhao Wen (ORCID: https://orcid.org/0000-0001-9879-7385)
- Dung‐Fang Lee (ORCID: https://orcid.org/0000-0003-2387-597X)
- Elisa Carrillo (ORCID: https://orcid.org/0000-0002-0419-395X)
- Claudio Soto (ORCID: https://orcid.org/0000-0002-3412-0524)
- Wenbo Li (ORCID: https://orcid.org/0000-0002-9042-5664)
- Yi-Ting Chen (ORCID: https://orcid.org/0009-0004-3917-6115)
- Xiaoyu Zhu (ORCID: https://orcid.org/0000-0002-3785-0004)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- University of California, Irvine (US)
- University of California San Diego (US)
- La Jolla Bioengineering Institute (US)
- The University of Texas Health Science Center (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1038/s41467-025-60378-0
- Citations
- 4
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- University of Texas Health Science Center at Houston
- McGovern Medical School
- National Institutes of Health
- Weill Cornell Medical College
- University of California, San Francisco
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases