Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes

作者：Cristina T. Vicente, Tejasvi Niranjan, Elise Coopman, Júlia Faura, Sara Alidadiani, Claudia Schrauwen, Billie J. Matchett, Bavo Heeman, Marleen Van den Broeck, Wouter De Coster, Thuy Nguyen, Julie S. Lau, Saurabh Baheti, Tim De Pooter, Peter De Rijk, Mojca Stražišar, Matt Baker, Mariely DeJesus‐Hernandez, NiCole A. Finch, Cyril Pottier, Marka van Blitterswijk, Yan W. Asmann, Melissa E. Murray, Leonard Petrucelli, Andrew King, Claire Troakes, Safa Al‐Sarraj, Robert A. Rissman, Annie Hiniker, Margaret E. Flanagan, Bret M. Evers, Charles L. White, Carlos Cruchaga, Rudolph J. Castellani, Jeroen van Rooij, Merel O. Mol, Harro Seelaar, John C. van Swieten, Björn Oskarsson, R. Ross Reichard, Aivi T. Nguyen, Keith A. Josephs, Ronald C. Petersen, Nilüfer Ertekin‐Taner, Bradley F. Boeve, Neill R. Graff‐Radford, Sarah Weckhuysen, Dennis W. Dickson, Rosa Rademakers · 发表于：Molecular Neurodegeneration · 年份：2025 · DOI：10.1186/s13024-025-00869-2 · 被引用次数：1 · 研究领域：Amyotrophic Lateral Sclerosis Research、Epigenetics and DNA Methylation、Neurological diseases and metabolism

BACKGROUND: In the last decade, the importance of DNA methylation in the functioning of the central nervous system has been highlighted through associations between methylation changes and differential expression of key genes involved in aging and neurodegenerative diseases. In frontotemporal lobar degeneration (FTLD), aberrant methylation has been reported in causal disease genes including GRN and C9orf72; however, the genome-wide contribution of epigenetic changes to the development of FTLD remains largely unexplored. METHODS: We performed reduced representation bisulfite sequencing of matched pairs of post-mortem tissue from frontal cortex (FCX) and cerebellum (CER) from pathologically confirmed FTLD patients with TDP-43 pathology (FTLD-TDP) further divided into five subtypes and including both sporadic and genetic forms (N = 25 pairs per group), and neuropathologically normal controls (N = 42 pairs). Case-control differential methylation analyses were performed, both at the individual CpG level, and in regions of grouped CpGs (differentially methylated regions; DMRs), either including all genomic locations or only gene promoters. Gene Ontology (GO) analyses were then performed using all differentially methylated genes in each group of sporadic patients. Finally, additional datasets were queried to prioritize candidate genes for follow-up. RESULTS: Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpG...