Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes.
Co-methylation
DNA methylation
EWAS
Frontotemporal dementia
Human brain tissue
Progressive supranuclear palsy
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
06
12
2022
accepted:
28
04
2023
revised:
28
04
2023
medline:
14
6
2023
pubmed:
7
5
2023
entrez:
7
5
2023
Statut:
ppublish
Résumé
Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5'UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.
Identifiants
pubmed: 37149835
doi: 10.1007/s00401-023-02583-z
pii: 10.1007/s00401-023-02583-z
pmc: PMC10261190
doi:
Substances chimiques
DNA
9007-49-2
tau Proteins
0
OTUD4 protein, human
EC 3.4.19.12
Ubiquitin-Specific Proteases
EC 3.4.19.12
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
77-95Subventions
Organisme : Medical Research Council
ID : MR/N013867/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R56 AG055824
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG068880
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS123743
Pays : United States
Informations de copyright
© 2023. The Author(s).
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