The YTHDF proteins modulate Alzheimer’s disease-associated brain gene signatures

Abstract 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.

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Publication Details

Journal
Molecular Neurodegeneration
Published
2026-09-05
DOI
https://doi.org/10.1186/s13024-026-00986-6
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
0.00
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article

The YTHDF proteins modulate Alzheimer’s disease-associated brain gene signatures

Shinya Tasaki, Nicholas T. Seyfried, Lisa L. Barnes, Sashini De Tissera et al.
Molecular Neurodegeneration
RNA modifications and cancer
article

The YTHDF proteins modulate Alzheimer’s disease-associated brain gene signatures

Shinya Tasaki, Nicholas T. Seyfried, Lisa L. Barnes, Sashini De Tissera, Chunjiang Yu, Himanshu Vyas, Daniel J. Flood, Artemis Iatrou, Nicola A. Kearns, Chris Gaiteri, Denis Avey, Jishu Xu, Aliza P. Wingo, Chuan He, Thomas S. Wingo, Katherine Rothamel, Gene W. Yeo, Lin Cheng, David A. Bennett, Yanling Wang, Philip L. De Jager, Wenlong Li
article en

Abstract

Abstract 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.

Molecular Neurodegeneration
Rush University Medical Center (US), Howard Hughes Medical Institute (US), Harvard University (US), Emory University (US), SUNY Upstate Medical University (US), McLean Hospital (US), University of California San Diego (US), University of Chicago (US), VA Northern California Health Care System (US), University of California, Davis (US)
Openalex Percentile: Top 17%
RNA modifications and cancer
DOIOpen Access PDFOpenAlex
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