Chromosome 9 open reading frame 72 transcriptional machinery (C9orf72 TM)

The Chromosome 9 open reading frame 72 (C9orf72) transcriptional machinery refers to the complex of proteins and regulatory factors, including RNA polymerase II and the elongation factor SUPT4H1, that govern the expression of the C9orf72 gene (UniProt Q96LT7). In patients with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), a pathogenic GGGGCC hexanucleotide repeat expansion in the first intron of this gene leads to the production of toxic sense and antisense RNA transcripts (PMID: 24191021). These transcripts form RNA foci that sequester essential RNA-binding proteins and undergo repeat-associated non-AUG (RAN) translation to produce neurotoxic dipeptide repeat proteins (DPRs) (PMID: 26385870). Therapeutic strategies targeting this machinery aim to selectively inhibit the transcription of these expanded repeats or degrade the resulting RNA products using antisense oligonucleotides (ASOs) like BIIB078 or WVE-004 (PMID: 33169018). A major challenge in drug development is achieving potent suppression of the toxic repeat-containing transcripts while maintaining sufficient levels of the endogenous C9orf72 protein, which is critical for normal endosomal trafficking and lysosomal function (PMID: 25126784).

Other names

C9orf72 transcriptional complexC9orf72 regulatory machinerySUPT4H1-mediated C9orf72 transcriptionG4C2 repeat transcription machinery

Inhibition of sense and antisense transcription of the GGGGCC hexanucleotide repeat expansion, degradation of repeat-containing RNA transcripts via RNase H-mediated cleavage, and suppression of non-canonical RAN translation to reduce dipeptide repeat protein levels.