EAGER: Controlling chromosome folding to understand and manipulate genome regulation

Are chromosomes randomly crammed inside the cell nucleus? No, far from it. In fact, the precise pattern of DNA folding is very important for how genes, which are scattered all across chromosomes, can function. For example, in addition to genes, chromosomes harbor a constellation of elements called “enhancers” that boost the activity of genes packaged with them in the nucleus. Thus, if chromosome folding brings a given gene together with an enhancer, the gene will be more active; whereas if they are separated, the gene will be less active. This project will establish novel tools based on the cohesin protein complex to artificially manipulate chromosome folding and modulate various genome functions – including enhancer regulation of gene expression. Such technologies can enable unprecedented control over chromosome structure and function, opening new avenues for both fundamental research as well as genome and epigenome engineering. Broader impacts of this project include multi-disciplinary research training opportunities for students from diverse backgrounds. Cohesin catalyzes DNA loop extrusion, which is central to the proper folding of chromosomes. This project will create tools to either force or disable cohesin-mediated looping at any desired genomic location and effectively enable re-folding of chromosomes in a designer fashion. The resulting technology will be used to explore novel ways to modulate, supplant or bypass how enhancers regulate genes. For example, control of DNA looping could be the basis of future strategies to prevent genes involved in cancer from being activated by neighboring enhancers in tumor cells. Gaining the ability to rewire the genome and control the many processes that rely on genome architecture holds promise for synthetic biology, biomedicine, and other research areas that advance biotechnology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.