DNA methylation and proteomic profiling of postmortem brain tissue reveals epigenetic dysregulation and inflammatory signaling in fragile X-associated tremor/ataxia syndrome.
9 affiliations
- 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 2Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 3Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 5Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 6Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 7Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
- 8MIND Institute and Department of Pediatrics, University of California Davis Health, Davis, Sacramento, CA, United States.
- 9Institute for Pediatric Regenerative Medicine, University of California Davis Health, Davis, Sacramento, CA, United States.
Abstract
Background
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a CGG repeat expansion in the premutation range of FMR1. The epigenetic landscape of the FXTAS brain remains largely uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex and targeted proteomic profiling to investigate molecular alterations associated with FXTAS and evaluate convergence on inflammatory signaling.Methods
DNA methylation was profiled in postmortem prefrontal cortex from 27 male FXTAS cases and 29 male controls using Illumina MethylationEPIC arrays. Surrogate variable analysis was used to account for latent sources of variation. Differentially methylated positions (DMPs) were defined as well as differentially methylated regions (DMRs). Exploratory functional analyses and comparison with published FXTAS transcriptomic and neurodegenerative-disease methylation datasets. Targeted proteomic profiling using the Olink Inflammation panel was performed in 9 male FXTAS cases and 12 male controls.Results
We identified 98 DMPs which mapped to 70 genes. Notable DMP-associated genes included CYP2E1, related to oxidative stress; TRAF3, BATF, RCOR1, and MSI2, with roles in immune and NF-κB-related signaling; and genes associated with myelination (LINGO1), synaptic function (SYT3), and zinc homeostasis (SLC39A4). TRAF3, a negative regulator of NF-κB and type I interferon signaling, contained one of the most significant DMPs. Exploratory Reactome analysis highlighted biological themes related to inflammatory resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism, although no pathway remained significant after multiple-testing correction. Transcription-factor motif enrichment and protein-protein interaction analyses identified no significant higher-order regulatory or interaction modules. Seven DMP-associated genes overlapped with differentially expressed genes from an independent FXTAS mouse transcriptomic study, whereas no gene-level overlap was detected with the Alzheimer's, Parkinson's, or Huntington's disease methylation signatures examined. Olink profiling identified 60 significantly altered inflammation-related proteins, 59 of which showed lower abundance in FXTAS, including TLR3, IRAK1, IRAK4, IKBKG/NEMO, and C1QA.Conclusion
These findings identify previously unrecognized DNA methylation alterations in FXTAS prefrontal cortex involving genes related to oxidative stress, myelination, zinc homeostasis, and innate immune/NF-κB signaling. Convergence between methylation changes in immune-regulatory genes, including TRAF3, and a predominantly reduced inflammatory protein signature provides complementary evidence for altered inflammatory signaling in FXTAS.
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BibTeX
@article{lozano2026methylation,
title = {{DNA methylation and proteomic profiling of postmortem brain tissue reveals epigenetic dysregulation and inflammatory signaling in fragile X-associated tremor/ataxia syndrome.}},
author = {Reymundo Lozano and Xiao Lin and Randi Hagerman and Verónica Martínez-Cerdeño and Dalila Pinto},
journal = {Frontiers in molecular neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnmol.2026.1932396},
url = {https://europepmc.org/article/MED/42947982},
note = {CC BY},
}
RIS
TY - JOUR
TI - DNA methylation and proteomic profiling of postmortem brain tissue reveals epigenetic dysregulation and inflammatory signaling in fragile X-associated tremor/ataxia syndrome.
AU - Reymundo Lozano
AU - Xiao Lin
AU - Randi Hagerman
AU - Verónica Martínez-Cerdeño
AU - Dalila Pinto
PY - 2026
DA - 2026/10/13
JO - Frontiers in molecular neuroscience
DO - 10.3389/fnmol.2026.1932396
UR - https://europepmc.org/article/MED/42947982
AB - Background Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a CGG repeat expansion in the premutation range of FMR1. The epigenetic landscape of the FXTAS brain remains largely uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex and targeted proteomic profiling to investigate molecular alterations associated with FXTAS and evaluate convergence on inflammatory signaling.Methods DNA methylation was profiled in postmortem prefrontal cortex from 27 male FXTAS cases and 29 male controls using Illumina MethylationEPIC arrays. Surrogate variable analysis was used to account for latent sources of variation. Differentially methylated positions (DMPs) were defined as well as differentially methylated regions (DMRs). Exploratory functional analyses and comparison with published FXTAS transcriptomic and neurodegenerative-disease methylation datasets. Targeted proteomic profiling using the Olink Inflammation panel was performed in 9 male FXTAS cases and 12 male controls.Results We identified 98 DMPs which mapped to 70 genes. Notable DMP-associated genes included CYP2E1, related to oxidative stress; TRAF3, BATF, RCOR1, and MSI2, with roles in immune and NF-κB-related signaling; and genes associated with myelination (LINGO1), synaptic function (SYT3), and zinc homeostasis (SLC39A4). TRAF3, a negative regulator of NF-κB and type I interferon signaling, contained one of the most significant DMPs. Exploratory Reactome analysis highlighted biological themes related to inflammatory resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism, although no pathway remained significant after multiple-testing correction. Transcription-factor motif enrichment and protein-protein interaction analyses identified no significant higher-order regulatory or interaction modules. Seven DMP-associated genes overlapped with differentially expressed genes from an independent FXTAS mouse transcriptomic study, whereas no gene-level overlap was detected with the Alzheimer's, Parkinson's, or Huntington's disease methylation signatures examined. Olink profiling identified 60 significantly altered inflammation-related proteins, 59 of which showed lower abundance in FXTAS, including TLR3, IRAK1, IRAK4, IKBKG/NEMO, and C1QA.Conclusion These findings identify previously unrecognized DNA methylation alterations in FXTAS prefrontal cortex involving genes related to oxidative stress, myelination, zinc homeostasis, and innate immune/NF-κB signaling. Convergence between methylation changes in immune-regulatory genes, including TRAF3, and a predominantly reduced inflammatory protein signature provides complementary evidence for altered inflammatory signaling in FXTAS.
SN - 1662-5099
ER -