Pioneer: Form and function of our Janus faced genome

A map, in one sense, is the demarcation of boundaries throughout a defined space. The quintessential maps of biology are: 1) the reference human genome, which delineated the fundamental topographic landscape of chromosomal DNA, and 2) the ENCODE project, which comprehensively annotated the functional elements residing within the chromosomal confine. Together, these powerful resources are an atlas of knowledge that enables navigation of the contours of the classic autosomal and allosomal human genome. Indeed, these efforts can be considered pioneering in large part because they built new maps, containing fundamentally new information, on which the vast expanse of current biomedical research can be contextualized. Ironically, these maps, while revolutionary, become constraining. There is reason to believe that the boundaries of the human genome range outside the known limits and have long remained uncharted. In true pioneering spirit, therefore, we will look beyond the chromosomal domain in an effort to elucidate the extrachromosomal human genome. As we detail in this grant proposal, deciphering the identity and functional impact of the extrachromosomal DNAs promises to unlock fundamental biological principles governing cellular function. We expect our proposed work will create new basic tenets of cell and molecular biology that will reshape long-standing assumptions about the directional flux of human genetic material embedded in the central dogma of biology. We will develop innovative targeting strategies to rigorously interrogate extrachromosomal DNA identity and function. This comprehensive suite of tools can also double as a novel therapeutic platform in the future of extrachromosomal DNA modulation. By expanding the encyclopedia of DNA biology, we seek to produce a groundbreaking addition to our understanding of the fundamental nature of cellular biology.