Many people are familiar with “genetics,” the inheritance of visible traits like eye and hair color. Traits are encoded by a molecular alphabet (A,T,C,G) in the well known double helix structure, DNA. Less well known, but quickly gaining attention, is the network of protein particles that interact with DNA to control the folding of chromosomes and the expression of inherited traits. This process is epi-genetics (epi, EH-pee = upon or above). Our research group uses gene and protein engineering to create new epigenetic machinery that regulates DNA at will. One day synthetic epigenetics may allow us to rationally design new biological systems with predictable, reliable behavior and replace “magic bullet medicine” with “smart medicine.”
We assemble interchangeable protein modules to build synthetic transcription factors that regulate gene activity in human cells. Unlike typical synthetic transcription factors that recognize specific DNA sequences, our Polycomb-based transcription factors (“PcTFs”) are engineered to read chromatin modifications. Thus, a single engineered TF could activate a group of silenced, therapeutic genes in cancer cells. Using strong gene activators could enhance cancer treatment and advance epigenetic medicine.
As synthetic biologists, our goal is to make the folded DNA-protein material, or chromatin (KRO-mah-tin = dark colored material in the nucleus of a fixed and stained cell), easier to design and engineer. Groups of genes often reside in the same compartments, and share the same DNA-protein packaging structures. Therefore, a small artificial change in one packaging protein can reprogram the expression of dozens, and even hundreds of genes. Is this outcome messy and useless, or is it a powerful mode of signal amplification that changes cells in useful ways? To answer this question, our group couples synthetic biology with bioinformatics by interrogating the expression of thousands of genes after we introduce artificial chromatin proteins into cells.