Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder with late clinical onset, despite the mutant Huntingtin gene (HTT) being present from birth.
• Transcriptional dysregulation is a key feature of HD, but the specific genes and regulators involved in the prodromal period are not fully understood.
• Identifying early molecular changes and their regulators presents opportunities for therapeutic intervention in HD.

Purpose of the Study:

• To investigate transcriptional and epigenetic alterations during the presymptomatic stages of Huntington's disease.
• To identify key regulatory factors driving these early molecular changes in HD.
• To evaluate the therapeutic potential of targeting identified regulators for alleviating HD pathology.

Main Methods:

• Transcriptional profiling and chromatin analysis (histone H3K27acetylation) in the striatum of R6/1 mouse models during presymptomatic stages.
• Integration of transcriptional and epigenetic data to identify candidate regulatory factors.
• Functional validation of candidate regulators using cell culture models and adeno-associated virus (AAV)-mediated gene delivery in mice.

Main Results:

• Aberrant transcription and altered histone H3K27acetylation were observed in the striatum of presymptomatic R6/1 mice.
• The Elk-1 transcription factor was identified as a key regulator associated with these early epigenetic and transcriptional changes in HD.
• Exogenous Elk-1 expression demonstrated beneficial effects in HD cell models and alleviated transcriptional dysregulation in R6/1 mice.

Conclusions:

• Aberrant gene expression precedes overt Huntington's disease onset.
• Elk-1 is a crucial regulator linked to early molecular pathology in HD.
• Targeting Elk-1 offers a promising therapeutic strategy for mitigating Huntington's disease progression.