| Title: |
Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes |
| Authors: |
Vicente, Cristina; Niranjan, Tejasvi; Coopman, Elise; Faura Llorens, Júlia; Alidadiani, Sara; Schrauwen, Claudia; Matchett, Billie J.; Heeman, Bavo; Van den Broeck, Marleen; De Coster, Wouter; Nguyen, Thuy; Lau, Julie S.; Baheti, Saurabh; De Pooter, Tim; De Rijk, Peter; Strazisar, Mojca; Baker, Matt; DeJesus-Hernandez, Mariely; Finch, NiCole A.; Pottier, Cyril; van Blitterswijk, Marka; Asmann, Yan; Murray, Melissa E.; Petrucelli, Leonard; King, Andrew; Troakes, Claire; Al-Sarraj, Safa; Rissman, Robert A.; Hiniker, Annie; Flanagan, Margaret; Evers, Bret M.; White, Charles L.; Cruchaga, Carlos; Castellani, Rudolph; van Rooij, Jeroen G.J.; Mol, Merel O.; Seelaar, Harro; van Swieten, John C.; Oskarsson, Björn; Reichard, Robert Ross; Nguyen, Aivi T.; Josephs, Keith A.; Petersen, Ronald C.; Ertekin-Taner, Nilüfer; Boeve, Bradley F.; Graff-Radford, Neill R.; Weckhuysen, Sarah; Dickson, Dennis W.; Rademakers, Rosa |
| Source: |
1750-1326 ; Molecular neurodegeneration |
| Publication Year: |
2025 |
| Collection: |
IRUA - Institutional Repository van de Universiteit Antwerpen |
| Subject Terms: |
Biology; Human medicine |
| Description: |
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 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/isi/001523167600001 |
| Availability: |
https://hdl.handle.net/10067/2158380151162165141; https://repository.uantwerpen.be/docstore/d:irua:30091 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.34BC13D8 |
| Database: |
BASE |