The same genetic blueprint gives rise to thousands of cell types that make up the human body. These cells must also be arranged properly to make tissues and organs. How one genome encodes thousands of patterns in space and time is of central importance to biology and medicine. Inappropriate activation of genes can give rise to birth defects, cancer, or premature aging, among many other diseases, and restoration of proper organ function often requires restoring homeostatic gene regulation.My group is interested in methods to predict, dissect, and control large-scale gene regulatory programs. Because site-specific differences in epithelia are encoded in the associated dermal fibroblasts, we study how fibroblasts maintain an address code of the body through a hierarchy of site-specific gene expression programs. We discovered long noncoding RNAs (lncRNAs) as novel regulators of positional memory that control the modification states of chromatin, the DNA-protein interface where genes reside. We are developing new computational methods to pinpoint genetic lesions that drive large-scale gene expression programs in cancers and in normal tissues. The ability to pinpoint regulators has enabled improved selection of targeted therapies in cancer, better understanding and direct creation of human cancer stem cells, and led to the identification of a genetic pathway that can be manipulated to reverse aging. Together, our studies are creating a holistic and mechanistic view of how the genome coordinates the control of thousands of genes over space and time.