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DNA methylation profiling in human Huntington's disease brain
Rebecca A G De Souza1, Sumaiya A Islam2, Lisa M McEwen2
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4 rdesouza@cmmt.ubc.ca.
Human Molecular Genetics
|March 9, 2016
Summary
Epigenetic variations in Huntington's disease (HD) brains are not clearly linked to pathogenesis. However, DNA methylation patterns in the huntingtin gene (HTT) promoter may influence tissue-specific gene expression, potentially involving CTCF.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- Huntington's disease (HD) pathogenesis and tissue-specific huntingtin gene (HTT) regulation remain poorly understood, particularly concerning epigenetic variations in human brain tissues.
- HTT expression is notably high in brain and testes, suggesting a need to investigate factors controlling its tissue-specific transcription.
Purpose of the Study:
- To investigate the role of DNA methylation in HD pathogenesis and the tissue-specific expression of the HTT gene.
- To explore potential associations between DNA methylation, HD, and the age of disease onset in human brain and liver tissues.
Main Methods:
- Utilized the Illumina HumanMethylation450K BeadChip array to measure DNA methylation in matched cortex and liver tissues from HD patients and controls.
- Analyzed DNA methylation data, corrected for cell heterogeneity, and assessed the association with age of disease onset.
- Investigated the role of the transcription factor CTCF in regulating HTT promoter activity using reporter constructs.
Main Results:
- Minimal evidence of HD-associated DNA methylation was found in cortex samples, but an association with the age of disease onset was observed.
- Identified 38 differentially methylated sites in the HTT gene region between cortex and liver tissues, indicating tissue-specific methylation.
- Discovered a novel CTCF binding site in the HTT promoter that shows differential occupancy between cortex and liver, and CTCF silencing affected HTT promoter activity.
Conclusions:
- While direct HD-associated DNA methylation alterations were not detected at queried sites, DNA methylation may correlate with the age of disease onset in cortex.
- DNA methylation appears to contribute to tissue-specific HTT transcription, potentially through differential CTCF transcription factor occupancy.
- CTCF plays a role in regulating HTT promoter function, highlighting its importance in tissue-specific gene expression.
