Huntingtin (HTT) promoter genomic DNA (HTT promoter)

The Huntingtin (HTT) promoter genomic DNA is the regulatory sequence located upstream of the HTT gene (also known as IT15) that controls the initiation of its transcription (Lin et al., 1993, PubMed: 8406445). This promoter is characterized by a high GC content and multiple Sp1 binding sites, functioning as a constitutive driver of HTT expression throughout the central nervous system (Coles et al., 1998, PubMed: 9634582). In Huntington's disease, a CAG repeat expansion in the first exon of the HTT gene leads to the production of a toxic mutant protein; therefore, the promoter serves as a strategic target for gene-silencing therapies (Tabrizi et al., 2020, PubMed: 31909244). Therapeutic modalities such as Zinc Finger Protein Transcription Factors (ZFP-TFs), like TAK-686, and CRISPR-based interference (CRISPRi) are designed to bind this region to repress transcription and lower mutant huntingtin levels (Zeitler et al., 2019, PubMed: 31263218). A primary challenge in targeting the HTT promoter is achieving allele-specific repression to avoid silencing the wild-type allele, which is vital for cellular health and neuroprotection (Saudou & Humbert, 2016, PubMed: 26935134). Success in targeting the HTT promoter could provide a long-term or permanent treatment for HD by addressing the disease at its genetic source.

Other names

HTT gene promoterHuntingtin gene promoterIT15 promoterHTT regulatory region

Transcriptional repression of the HTT gene to reduce the production of mutant huntingtin protein.