Transcriptional dysregulation is a hallmark of [Huntington's disease](/diseases/huntingtons) (HD) pathogenesis. Mutant huntingtin (mHTT) disrupts gene expression through multiple interconnected mechanisms including direct sequestration of transcription factors, interference with coactivators, altered chromatin structure, and disruption of neuronal gene programs. This pathway describes the molecular cascade from mHTT accumulation to widespread transcriptional dysfunction in striatal and cortical neurons.
Pathway Diagram
flowchart TD
A["Mutant Huntingtin<br/>mHTT Accumulation"] --> B["Direct Protein Interactions"]
A --> C["Indirect Mechanisms"]
B --> D["Transcription Factor Sequestration<br/>Sp1, TAFII130, p53, REST"]
B --> E["Coactivator Sequestration<br/>CBP, NCoA, PCAF"]
C --> F["Altered Chromatin Structure<br/>Histone modifications"]
C --> G["Mitochondrial Dysfunction<br/>PGC-1alpha disruption"]
C --> H["Nucleocytoplasmic Transport Defects"]
D --> I["Gene Expression Changes<br/>Up/Downregulation"]
E --> I
F --> I
G --> I
H --> I
I --> J["Neuronal Dysfunction<br/>Synaptic deficits"]
I --> K["Cell Death Pathways<br/>Apoptosis"]
click A "/genes/htt" "HTT Gene"
click I "/mechanisms/transcriptional-dysregulation" "General Transcriptional Dysregulation"
click K "/mechanisms/mitochondrial-dysfunction" "Mitochondrial Dysfunction"
click D "/mechanisms/htt-huntingtin-hd-causal-chain" "HTT Causal Chain"
Molecular Mechanisms
...
HTT Transcriptional Dysregulation Pathway
Overview
Transcriptional dysregulation is a hallmark of [Huntington's disease](/diseases/huntingtons) (HD) pathogenesis. Mutant huntingtin (mHTT) disrupts gene expression through multiple interconnected mechanisms including direct sequestration of transcription factors, interference with coactivators, altered chromatin structure, and disruption of neuronal gene programs. This pathway describes the molecular cascade from mHTT accumulation to widespread transcriptional dysfunction in striatal and cortical neurons.
Pathway Diagram
Mermaid diagram (expand to render)
Molecular Mechanisms
Step 1: Direct Sequestration of Transcription Factors
Mutant huntingtin directly binds to and sequesters several transcription factors, altering their nuclear availability and function:
REST/NRSF Dysregulation
The most well-characterized interaction is with REST (RE1-silencing transcription factor, also known as NRSF):[@zuccato2003]
Normal function: Wild-type huntingtin sequesters REST in the cytoplasm, preventing REST from entering the nucleus
In HD: Mutant huntingtin loses this function, allowing REST to translocate to the nucleus
Consequence: REST represses neuronal genes, particularly those encoding neurotrophic factors like [BDNF](/proteins/bdnf-protein)