The YTHDF proteins modulate Alzheimer’s disease-associated brain gene signatures
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.
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Authors: Shinya Tasaki, Denis Avey, Nicola A. Kearns, Chunjiang Yu, Sashini De Tissera, Himanshu Vyas, Lin Cheng, Jishu Xu, Artemis Iatrou, Daniel J. Flood, Wenlong Li, Lisa L. Barnes, Katherine Rothamel, Aliza P. Wingo, Thomas S. Wingo, Nicholas T. Seyfried, Chuan He, Philip L. De Jager, Gene W. Yeo, Chris Gaiteri, David A. Bennett, Yanling Wang
Institutions: University of Chicago, University of California San Diego, Harvard University, Emory University, University of California, Davis, Howard Hughes Medical Institute, Rush University Medical Center, SUNY Upstate Medical University, McLean Hospital, VA Northern California Health Care System