Targeted epigenetic editing for reprograming of complex phenotypes in breast cancer

The completion of genome, epigenome and transcriptome mapping in multiple cell types has created a demand for precision biomolecular tools that allow researchers to functionally manipulate DNA, reconfigure chromatin structure and ultimately reshape gene expression patterns. Here we will describe the generation of epigenetic editing tools to interrogate the relationship between epigenetic modifications and gene expression, and to functionally map regulatory regions such as promoters and enhancers, for both coding genes and small non-coding RNAs. Importantly, the reversible characteristics of epigenetic modifications offer an attractive therapeutic opportunity to reprogram complex phenotypes, such as metastatic behavior, via targeted epigenome engineering.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins adapted for epigenetic editing provides an unprecedented tool to regulate multiple genes and reprogram cell phenotypes. In this system catalytically defective dCas9 is fused to epigenetic modifying domains to target specific epigenetic marks to specific sites in the genome. Epigenetic editing of multiple tumour suppressor genes and oncogenes will be discussed, particularly for the reprograming of complex yet plastic and reversible gene programs such as epithelial-to-mesenchymal transition (EMT) in breast cancer. Finally, we will describe the development of novel tumour-specific delivery systems for CRISPR in mouse tumour models and outline potential applications for the future treatment of metastatic breast cancers for which no cure is available.