Human genomic DNA is the ultimate blueprint of our heredity. The genetic information of thehuman genome holds the key to our most fundamental questions in human biology of health and disease. The grand challenge in the post genomic era is to translate the information encoded in the genes and gene products of the human genome into an understanding of their functions in cellular physiology and pathophysiology, and into new medicine. However, our current knowledge about the regulation and transduction of genetic information is very limited.

Understanding of genetic regulation that is also governed by information not encoded in the DNA sequence - the essence of epigenetics - would demand creative approaches to genomic science. Such innovative approaches require the generation of not only an extremely large amount of new knowledge on structure-function and mechanisms of chromosomal proteins on the genomic scale, but also the means to develop selective small-molecule probes to enable investigation of biological functions of endogenous proteins under physiological conditions as pertained to the epigenetic regulation.

Our research being developed with multifaceted and integrative approaches aims to address the biology of epigenetic regulation of the human genome to attain both mechanistic insight and the rational design of small-molecule probes that target chromosomal proteins. The emphasis is on the role of histone-mediated molecular interaactions and modifications in chromatin biology.

To this end, we develop an interdisciplinary genomics research paradigm to conduct genome-wide functional profiling of chromosomal proteins in epigenetic gene regulation - an emerging field that we term Structural & Chemical Epigenomics. This paradigm relies on combined experimental and computational approaches to structural and chemical biology, as well as molecular and cellular chromatin biology. Not only will these studies provide the means to better understand gene regulatory patterns at the most basic molecular level of human health and disease, but also address the fundamental questions about the biological and physiological complexity of humans whose genome contains about 30,000 protein-coding genes that merely doubles that of the Drosophila melanogaster. To attain these goals, we conduct simultaneously three interdependent areas of genomic research: (1) Genome-wide molecular profiling of chromosomal proteins in histone recognition and modifications; (2) Structure-based functional design of small-molecule chemical probes for chromosomal proteins; and (3) Chemical epigenomics study of histone-directed chromatin biology.