The genome-wide activity of transcription factors (TFs) on multiple regulatory elements precludes their use as gene-specific regulators. Here we show that ectopic expression of a TF in a cellspecific context can be used to silence the expression of a specific gene as a therapeutic approach to regulate gene expression in human disease. We selected the TF Krüppel-like factor 15 (KLF15) based on its putative ability to recognize a specific DNA sequence motif present in the rhodopsin (RHO) promoter and its lack of expression in terminally differentiated rod photoreceptors (the RHO-expressing cells). Adeno-associated virus (AAV) vector–mediated ectopic expression of KLF15 in rod photoreceptors of pigs enables Rho silencing with limited genome-wide transcriptional perturbations. Suppression of a RHO mutant allele by KLF15 corrects the phenotype of a mouse model of retinitis pigmentosa with no observed toxicity. Cell-specific-context conditioning of TF activity may prove a novel mode for somatic gene–targeted manipulation.

Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15 / Botta, Salvatore; Nicola de Prisco, ; Marrocco, Elena; Renda, Mario; Sofia, Martina; Curion, Fabiola; Maria Laura Bacci, ; Ventrella, Domenico; Wilson, Cathal; Gesualdo, Carlo; Rossi, Settimio; Simonelli, Francesca; Enrico Maria Surace,. - In: JCI INSIGHT. - ISSN 2379-3708. - ELETTRONICO. - 2:24(2017), pp. 1-10. [10.1172/jci.insight.96560]

Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15

Maria Laura Bacci;Domenico Ventrella;
2017

Abstract

The genome-wide activity of transcription factors (TFs) on multiple regulatory elements precludes their use as gene-specific regulators. Here we show that ectopic expression of a TF in a cellspecific context can be used to silence the expression of a specific gene as a therapeutic approach to regulate gene expression in human disease. We selected the TF Krüppel-like factor 15 (KLF15) based on its putative ability to recognize a specific DNA sequence motif present in the rhodopsin (RHO) promoter and its lack of expression in terminally differentiated rod photoreceptors (the RHO-expressing cells). Adeno-associated virus (AAV) vector–mediated ectopic expression of KLF15 in rod photoreceptors of pigs enables Rho silencing with limited genome-wide transcriptional perturbations. Suppression of a RHO mutant allele by KLF15 corrects the phenotype of a mouse model of retinitis pigmentosa with no observed toxicity. Cell-specific-context conditioning of TF activity may prove a novel mode for somatic gene–targeted manipulation.
2017
Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15 / Botta, Salvatore; Nicola de Prisco, ; Marrocco, Elena; Renda, Mario; Sofia, Martina; Curion, Fabiola; Maria Laura Bacci, ; Ventrella, Domenico; Wilson, Cathal; Gesualdo, Carlo; Rossi, Settimio; Simonelli, Francesca; Enrico Maria Surace,. - In: JCI INSIGHT. - ISSN 2379-3708. - ELETTRONICO. - 2:24(2017), pp. 1-10. [10.1172/jci.insight.96560]
Botta, Salvatore; Nicola de Prisco, ; Marrocco, Elena; Renda, Mario; Sofia, Martina; Curion, Fabiola; Maria Laura Bacci, ; Ventrella, Domenico; Wilson, Cathal; Gesualdo, Carlo; Rossi, Settimio; Simonelli, Francesca; Enrico Maria Surace,
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/614148
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