Year 5
The physiological template of our genome, called chromatin, is composed of DNA wrapped around histone proteins. In the process of development the genome is interpreted in a way that is dynamic, and yet, often heritable, to produce different specialized tissues and organs. A substantial portion of information that is required for proper interpretation of the genome is transmitted in a form of histone modifications. Specific combinations of chemical modifications of histones form a basis of epigenetic marking system, which helps to organize the genome into functional domains, some of which are active, while others are silenced. These marking patterns can be harnessed to discover genomic regulatory elements involved in human development and disease. Indeed, less than 2% of the human genome encodes protein-coding genes. But many trait-specific and disease specific mutations seem to map away from such coding sequences. This paradox is partially resolved by observation that some of the noncoding sequences are involved in regulation of when and where in the developing organism genes are to be turned on and off. One class of such regulatory sequences is called enhancers, since they have a property to greatly enhance gene expression. With CIRM funding we characterized enhancer repertoires utilized by human embryonic cell types such as embryonic stem cells, neuroectoderm and neural crest. From these analyses we made interesting novel observations regarding gene regulation during human embryogenesis. We are now trying to understand how variation in regulatory elements and factors recognizing these elements contributes to developmental disorders.