? In order for the clinical potential of somatic and embryonic stem cells to be realized, the generation of tissues through efficient directed differentiation of stem cells is critical. Cellular differentiation is a fundamental aspect of metazoan biology that enables the elaboration of a complex multicellular organism from a single fertilized oocyte and prevents neoplastic expansion of somatic cell populations. It proceeds by a series of cell fate choices that must be encoded by the cell's epigenetic memory. Our long term goal is to identify the fundamental epigenetic structures that underlie the process of cellular differentiation and characterize the dynamics of their regulation. ? The specific aims are designed to identify differentiation-specific patterns of chromatin structure on a broad scale and characterize the dynamics of those changes during cellular differentiation: ? 1. Demonstrate a differentiation-specific pattern of histone modifications at promoter regions of a panel of hematopoietic genes. ? 2. Design, produce and test a murine promoter-focused DMA microarray for genome-scale analysis of chromatin structure. ? 3. Characterize changes in the global pattern of chromatin structure induced by hematopoietic and embryonic stem cell differentiation. ? These studies will provide fundamental insights into the regulatory logic that governs cellular differentiation and will be directly applicable to the fields of stem cell-based cellular therapeutics and clinical oncology. The specific hypothesis under investigation in the current application is that cell fate choices are accompanied by lineage-specific alterations in the global pattern of chromatin structure and this pattern of chromatin structure determines the potential for further differentiation ? ?
