Molecular neurodegeneration · 2026
The YTHDF proteins modulate Alzheimer's disease-associated brain gene signatures.
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Tasaki Shinya, Avey Denis R, Kearns Nicola A, Yu Chunjiang, Tissera Sashini De, Vyas Himanshu, Cheng Lin, Xu Jishu, Iatrou Artemis, Flood Daniel J, Li Wenlong, Barnes Lisa L, Rothamel Katherine, Wingo Aliza P, Wingo Thomas S, Seyfried Nicholas T, He Chuan, De Jager Philip L, Yeo Gene W, Gaiteri Chris, Bennett David A, Wang Yanling
Аннотация
Gene signatures of Alzheimer's disease (AD) brains reflect the output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To nominate candidate factors modulating these signatures, we developed a machine learning model to integrate cellular and molecular features explaining differential gene expression in AD. Among the features tested, YTHDF proteins, the canonical readers of N6-methyladenosine (m6A) RNA modification, are among the most influential predictors of AD gene signatures. Protein modules containing YTHDFs were downregulated in human AD brains, and knockdown or pharmacological inhibition of YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulated key AD-associated gene signatures. Furthermore, eCLIP-seq revealed altered YTHDF binding to transcripts in AD brains, at both m6A-dependent and m6A-independent sites. Together, these results support an important role for YTHDF proteins in modulating AD-associated gene signatures in the human brain.