Our goals during the next 5 year period are:||1. to study the regulation of tissue-specific genes during the progression from the pluripotent embryonic stem (ES) cell to fully differentiated cells||2. to investigate the mechanisms that underlie differentiation and programmed cell death of plasma cells and to use the insights gained from this study to identify potential therapeutic targets for treating multiple myeloma. ||The specific aims of the programme are:||1. Dissection of the epigenetic mechanisms that act on tissue-specific genes in pluripotent ES cells and prime them for expression at later stages. Investigation of the structure and regulation of a number of complex gene loci in ES cells and multipotent neural and mesenchymal stem cells.||2. Analysis of the interactions between stage-specific transcription factors and epigenetic marks at tissue-specific genes during stem cell commitment and differentiation. Investigation of the role of specific combinations of histone modifications in silencing gene expression and establishing and maintaining facultative heterochromatin during the progression from stem cells to fully differentiated cell types.||3. Analysis of the mechanisms of gene silencing by the transcription factors Ikaros and Aiolos during B cell development using the mouse 5-VpreB1 locus as a model system. Dominant negative mutant forms of Ikaros have been implicated in acute lymphoblastic leukaemia (ALL) and a better understanding of its mechanism of action is likely to provide insights into the role that Ikaros plays in the development of ALL. ||4. Investigation of the mechanisms of differentiation and programmed cell death of short-lived plasma cells. Analysis of apoptotic mechanisms in multiple myeloma cells under normal conditions and in response to chemotherapeutic agents.||