We create synthetic molecules that can be programmed to bind different DNA sequences and recruit specific cellular machines to the targeted genomic loci. When targeted to gene promoters and enabled to recruit the transcriptional machinery, these molecules can switch on the expression of proximal genes. Thus, they function as synthetic transcription factors (SynTFs). We have used this strategy to target the GAAGAAGAA trinucleotide repeat sequence that acts as a roadblock for transcriptional machinery in the Frataxin (FXN) gene. Blocking the expression of this gene causes an incurable brain disease called Friedreich’s ataxia. Our FXN targeted Syn-TFs display the ability to specifically overcome this barrier to transcriptional elongation of this gene without perturbing the expression of other genes in the genome. The ability to restore frataxin expression in patient-derived cells is now guiding the design of next-generation SynTFs to understand the etiology of and to precision-tailor remedies for a wide-range of human diseases.
References: Erwin et al. (2017) Science. 358:1617-1622.