Home > Publications Database > DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci. > print

001     279453
005     20250720001557.0
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041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Rambarack, Naiomi
|b 0
245 _ _ |a DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci.
260 _ _ |a London
|c 2025
|b Biomed Central
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520 _ _ |a Frontotemporal lobar degeneration (FTLD) represents a spectrum of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders. The two major FTLD pathological subgroups are FTLD-TDP and FTLD-tau. While the majority of FTLD cases are sporadic, heterogeneity also exists within the familial cases, typically involving mutations in MAPT, GRN or C9orf72, which is not fully explained by known genetic mechanisms. We sought to address this gap by investigating the effect of epigenetic modifications, specifically DNA methylation variation, on genes associated with FTLD genetic risk in different FTLD subtypes. We used frontal cortex DNA methylation profiles from three FTLD datasets containing different subtypes of FTLD-TDP and FTLD-tau: FTLD1m (N = 23) containing FTLD-TDP C9orf72 mutation carriers and sporadic cases, FTLD2m (N = 48) containing FTLD-Tau MAPT mutation carriers, FTLD-TDP GRN and C9orf72 mutation carriers, and FTLD3m (N = 163) sporadic FTLD-Tau (progressive supranuclear palsy - PSP) cases, and corresponding controls. We then leveraged FTLD transcriptomic and proteomic datasets to investigate possible downstream effects of DNA methylation changes. Our analysis revealed shared promoter region hypomethylation in STX6 across FTLD-TDP and FTLD-tau subtypes, though the largest effect size was observed in PSP cases compared to controls (delta-beta = -32%, FDR adjusted-p value = 0.002). We also observed dysregulation of the STX6 gene and protein expression in some FTLD subtypes. Additionally, we performed a detailed examination of MAPT, GRN and C9orf72 across subtypes and observed nominally significant differentially methylated CpGs in variable positions across the genes, often with unique patterns and downstream changes in gene/protein expression in mutation carriers. We highlight aberrant DNA methylation at different CpG sites mapping to genes previously associated with genetic risk of FTLD, including STX6. Our findings support convergence of genetic and epigenetic factors towards disruption of risk loci, bringing new insights into the contribution of these mechanisms to FTLD.
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650 _ 7 |a DNA methylation
|2 Other
650 _ 7 |a Disease risk
|2 Other
650 _ 7 |a Epigenetics
|2 Other
650 _ 7 |a Frontotemporal Lobar degeneration
|2 Other
650 _ 7 |a Frontotemporal dementia
|2 Other
650 _ 7 |a Neurodegeneration
|2 Other
650 _ 7 |a Progressive supranuclear palsy
|2 Other
650 _ 7 |a Qa-SNARE Proteins
|2 NLM Chemicals
650 _ 7 |a C9orf72 Protein
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a C9orf72 protein, human
|2 NLM Chemicals
650 _ 7 |a MAPT protein, human
|2 NLM Chemicals
650 _ 7 |a Progranulins
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a DNA Methylation: genetics
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: genetics
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Qa-SNARE Proteins: genetics
|2 MeSH
650 _ 2 |a Qa-SNARE Proteins: metabolism
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Genetic Predisposition to Disease: genetics
|2 MeSH
650 _ 2 |a C9orf72 Protein: genetics
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Progranulins: genetics
|2 MeSH
700 1 _ |a Fodder, Katherine
|b 1
700 1 _ |a Murthy, Megha
|b 2
700 1 _ |a Toomey, Christina
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700 1 _ |a de Silva, Rohan
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700 1 _ |a Heutink, Peter
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700 1 _ |a Humphrey, Jack
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700 1 _ |a Raj, Towfique
|b 7
700 1 _ |a Lashley, Tammaryn
|b 8
700 1 _ |a Bettencourt, Conceição
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773 _ _ |a 10.1186/s40478-025-02071-3
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