Faculty, Staff and Student Publications
Publication Date
6-6-2025
Journal
Nature Communications
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.
Keywords
Humans, Alzheimer Disease, RNA, Antisense, Neurons, tau Proteins, Promoter Regions, Genetic, Adenosine, RNA, Messenger, Brain, Gene Expression Regulation, Induced Pluripotent Stem Cells, Male, Female, Aged
DOI
10.1038/s41467-025-60378-0
PMID
40480976
PMCID
PMC12144123
PubMedCentral® Posted Date
6-6-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes