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 Strazisar, Matt Baker, Mariely DeJesus-Hernandez, NiCole A. Finch, Cyril Pottier, Marka van Blitterswijk, Yan Asmann, Melissa E. Murray, Leonard Petrucelli, Andrew King, Claire Troakes, Safa Al-Sarraj, Robert A. Rissman, Annie Hiniker, Margaret Flanagan, Bret M. Evers, Charles L. White, Carlos Cruchaga, Rudolph Castellani, Jeroen G.J. van Rooij, Merel O. Mol, Harro Seelaar, John C. van Swieten, Björn Oskarsson, Robert 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
{"title":"Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes","authors":"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 Strazisar, Matt Baker, Mariely DeJesus-Hernandez, NiCole A. Finch, Cyril Pottier, Marka van Blitterswijk, Yan Asmann, Melissa E. Murray, Leonard Petrucelli, Andrew King, Claire Troakes, Safa Al-Sarraj, Robert A. Rissman, Annie Hiniker, Margaret Flanagan, Bret M. Evers, Charles L. White, Carlos Cruchaga, Rudolph Castellani, Jeroen G.J. van Rooij, Merel O. Mol, Harro Seelaar, John C. van Swieten, Björn Oskarsson, Robert 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","doi":"10.1186/s13024-025-00869-2","DOIUrl":null,"url":null,"abstract":"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. 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. Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpGs (FCX = 6,520; CER = 7,134) and several hundred DMRs in FTLD-TDP brains (FCX = 134; CER = 219). Of these, less than 10% are shared between pathological subgroups. Combining additional datasets, we identified, validated and replicated hypomethylation of CAMTA1 in TDP-A potentially also impacting additional genes in the locus. GO analysis further implicated DNA methylation in myelination and developmental processes, as well as important disease-relevant mechanisms with subtype specificity such as protein phosphorylation and DNA damage repair in TDP-A, cholesterol biosynthesis in TDP-B, and protein localization in TDP-C. We identify methylation changes in all FTLD-TDP patient groups and show that most changes are unique to a specific pathological FTLD-TDP subtype, suggesting that these subtypes not only have distinct transcriptomic and genetic signatures, but are also epigenetically distinct. Our study constitutes an invaluable resource to the community and highlights the need for further studies to profile additional epigenetic layers within each FTLD-TDP pathological subtype.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"46 1","pages":""},"PeriodicalIF":17.5000,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Neurodegeneration","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13024-025-00869-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
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. 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. Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpGs (FCX = 6,520; CER = 7,134) and several hundred DMRs in FTLD-TDP brains (FCX = 134; CER = 219). Of these, less than 10% are shared between pathological subgroups. Combining additional datasets, we identified, validated and replicated hypomethylation of CAMTA1 in TDP-A potentially also impacting additional genes in the locus. GO analysis further implicated DNA methylation in myelination and developmental processes, as well as important disease-relevant mechanisms with subtype specificity such as protein phosphorylation and DNA damage repair in TDP-A, cholesterol biosynthesis in TDP-B, and protein localization in TDP-C. We identify methylation changes in all FTLD-TDP patient groups and show that most changes are unique to a specific pathological FTLD-TDP subtype, suggesting that these subtypes not only have distinct transcriptomic and genetic signatures, but are also epigenetically distinct. Our study constitutes an invaluable resource to the community and highlights the need for further studies to profile additional epigenetic layers within each FTLD-TDP pathological subtype.
期刊介绍:
Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels.
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.