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

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