Year 2

The human ES cells have the remarkable properties of self-renewal and unlimited potential to differentiate into other cell types in the body. Cell fate determination in ES cells involves selective activation and silencing of specific genes, a process that is accompanied by dynamic modifications of the histone proteins. Among the histone modifications that take place during ES cell differentiation are establishment of unique chromatin signatures at a class of regulatory DNA known as enhancers. Currently, the molecular mechanisms leading to the formation of characteristic histone modification signatures at enhancers are unknown. The proposed project is aimed to answer this question. We hypothesize that enhancer function requires binding of sequence specific transcription factors that recruit histone modification enzymes responsible for the unique histone modification pattern at these sequences. We also hypothesize that the histone modifications at enhancers in turn facilitate recruitment of chromatin binding proteins and possibly additional transcription factors to mediate transcriptional activation. During the second year of the five-year project, we have been able to identify one putative chromatin-modifying enzyme recruited to the enhancers and possibly involved in establishing the chromatin modification signature there. We have also identified a potential effector protein that bind to the chromatin modification at enhancers and potentially participate in the transcription activation of target genes. The research lays a foundation for mechanistic study of transcriptional enhancers in the human ES cells.