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. Genomic DNA in the cells is physically organized in the form of chromatin, which consists of DNA wrapped around histone proteins. 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.
We are studying how enhancer chromatin is dynamically regulated during development. In particular, embryonic stem cells have unique enhancer marking patterns, which dynamically change upon differentiation. In this reporting period we developed a dynamic system in which we can explore mechanisms by which enhancers are turned on and off. Using this system, we investigated changes in specific histone marks and in nucleosomal occupancy, accompanying enhancer activation in response to change in signaling environment.