Gene Specific Activation Driven by Small Molecules

Differing levels of chromatin compaction throughout the genome contribute to cell specificity and function. The importance of studying this complex processes is highlighted by the frequency of chromatin dysregulation in human diseases, which has led to the development of chromatin-based therapies in the clinic. To study this pathway, we designed a novel chemical-based system to redirect specific chromatin modifying machinery in a targeted and reversible manner. We synthesized a new class of bi-functional compounds, Chemical Epigenetic Modifiers (CEM)s, with one warhead arm that engages endogenous chromatin regulators, while the other targeting arm tethers the captured epigenetic regulatory machinery to the gene of interest. By redirecting endogenous chromatin regulatory machinery, we are able to control expression in a gene-specific manner. Genome-wide profile for BRD4 in 293 HEK cells following a 48 hour treatment with CEM87, a bifunctional molecule that binds and redirects endogenous BRD4 to a specific locus via dCas9-CEM interaction. RNA-seq in 293 HEK (4 samples)