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Epigenetic engineering cancer immunotherapy
The Novina lab has focused on the molecular mechanisms of microRNAs and their dysregulation in cancers. Indeed, it is critical to understand how microRNA expression is controlled in normal and disease contexts. In mammals, many microRNAs are developmentally regulated and demonstrate altered epigenetic profiles, such as aberrant promoter hypo- and hyper-methylation, in cancers. Altered microRNA expression has been correlated with the tissue of origin, prognosis, and drug sensitivity of cancers and other diseases. To study the causes and consequences of inappropriate DNA methylation of microRNA and other disease-causing genes, the Novina lab is developing "epigenetic engineering" tools that will facilitate site-specific addition and removal of methyl groups on DNA.
To accomplish this, we have been employing the RNA-directed CRISPR-Cas9 system. There are two key components to this system that can be leveraged for epigenetic reprogramming: (1) the Cas9 protein is directed to specific DNA sequences by a complementary guide RNA (gRNA). Introducing multiple gRNAs can direct Cas9 to multiple sites within a promoter or to multiple different promoters simultaneously. (2) Cas9 is normally an endonuclease that cleaves foreign DNA; however, an endonuclease-deficient Cas9 (dCas9) mutant allows localization of dCas9 without cleavage. To methylate or demethylate DNA at precise sites in the genome, we have fused methyltransferases (MTases) or demethylases to dCas9. To avoid deleterious effects of off-target methylation/demethylation, we took a "split-fusion" approach in which the enzyme is split into two inactive halves that only regain functionality when co-recruited to a particular site. These dCas9-fusion proteins bound to selected gRNAs will allow us to specifically target discrete loci for repression (methylation) or induction (demethylation) of genes of interest.
Precise control over DNA methylation will enable specific reprogramming of cell fates for experimental and therapeutic purposes. My lab is using these tools to (1) relate differential promoter methylation to changes in chromatin architecture and transcription factor binding at promoters; (2) compare methylation-dependent changes in microRNA transcription to oncogenic phenotypes; and (3) develop epigenetic reprogramming strategies for a variety of human diseases. A major initiative in my lab is using dCas9-MTases to target genes that repress immune responses. Our goal is to silence repressive protein-coding and non-coding genes to improve the efficacy of T cell-based cancer immunotherapy. We believe that a robust platform for epigenetic engineering will enable novel therapies against cancer and other diseases.
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