Epigenetic editing as a potential therapeutic tool for the treatment of noncommunicable diseases

Abstract

Epigenetic editing has a powerful potential to direct reprogramming of cellular phenotype that can be used in disease modeling. The reprogramming of cells from different origin into insulin-producing cells could provide a solution for restoring functional beta cell mass in diabetic patients. We used CRISPR/dCas9-based epigenetic tool for targeted hypermethylation of Arx promoter and its subsequent suppression in mouse pancreatic α cell line. By epigenetic silencing of Arx we successfully triggered a direct, transient switch of pancreatic α- to insulin-producing cells obtaining approximately 1% of transiently transfected cells which were able to produce 35% more insulin than Mock transfected α cells. As a future perspective we intend to address the potential use of epigenetic editing tool as a pre-therapeutic approach in triple-negative breast cancers (TNBCs) with unknown mutational signature of BRCA1. The BRCA1methylation (BRCAness) as a predictor for response to therapeutics such as PARPi would allow direct TNBC treatment without previous screening for BRCA1 mutations. The main objective will be to induce BRCAness by suppressing BRCA1 expression in TNBC cells via targeted DNA methylation of BRCA1 promoter using the synthetic epigenetic editing tool. This approach would enable the faster decision toward the use of newest medicaments to increase cells’ apoptosis and cancer cell diminishment.