The grand challenge in post genomic biomedical research is to translate the information encoded in genes and gene products of the human genome into an understanding of their functions in cellular physiology and patho- physiology, and into new approaches to medicine. However, our current knowledge is limited about the regulation and transduction of the genetic information that is believed to be governed by heritable information not encoded in the genomic DNA sequence - the essence of epigenetics. The long-term goal of our research is to develop innovative tools and technologies for the genomic scale study of epigenetic regulation of the human genome. Recent studies show that gene activation or silencing in response to physiological and environmental stimuli is dictated by chemical modifications of the DNA (i.e. methylation of cytosine) and of the chromosomal DNA-packing histones (i.e. acetylation, methylation, phosphorylation and ubiquitination). A unifying model has emerged to suggest an """"""""epigenetic code"""""""" embedded in chromatin that signifies regions of distinct nuclear activities such as heterochromatin formation or transcriptional activation. This enigmatic code is established by chromatin modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of the methyl-CpG binding domain, the bromodomain that """"""""reads"""""""" acetyl-lysine in histones, and the chromodomain or the PHD finger for methyl-lysine provides supporting evidence for this working hypothesis. To understand the fundamental principles that govern epigenetic gene regulation, new methodologies and innovative tools are needed for genome-wide investigation of chromosomal proteins in physiological conditions as pertained to the epigenetic regulation. Towards this goal, we propose to develop a new chemical genomics paradigm for structure-based functional design of small-molecule probes for histone binding proteins. This paradigm relies on a coherent set of experimental and computational methods of structural and chemical biology, and molecular/cell chromatin biology that are being developed in collaborations among the key investigators focused on the study of this system. As the new paradigm couples ligand design to genome-wide functional profiling of chromosomal proteins in epigenetic control, we term it Chemical Epigenomics. We expect that the new chemical tools and technologies emerging from this study will help address questions such as how histone modifications lead to regulatory capabilities of the chromatin in directing gene silencing or activation.
We aim to attain the following three Specific Aims: ? 1. Genome-wide profiling of chromosomal protein domains in histone recognition ? 2. Structure-based functional design of chemical probes ? 3. Chemical epigenomics study of histone-directed chromatin biology ? ?
The regulation and transduction of genetic information of the human genome, of which our current knowledge is limited despite the available near complete genome sequence information, is governed by information not only encoded in the DNA sequence, but also by the epigenetic information that is heritable in the complex chemical modifications of the DNA as well as the chromosomal DNA-packing histones. In this project, we propose to develop innovative tools and technologies that are required for the generation of an extremely large amount of new knowledge on structure-function and mechanisms of chromosomal proteins on the genomic scale, and also the means to develop novel selective small-molecule chemical probes to enable investigation of biological functions of chromosomal proteins in their endogenous forms and under physiological conditions as pertained to the epigenetic gene regulation a new genomics research paradigm we term Chemical Epigenomics. We expect that the emerging inferences on the Chemical Epigenomics study of the histone- directed chromatin biology have broad implications on further investigations that range from new understanding of the fundamental human epigenetics, stem cell identity and fate to the new development of novel epigenetic therapies to human disease. ? ? ?
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