The overall objective of this proposal is to develop strategies for deriving glucose-responsive insulin-producing (-cells from human embryonic stem (hES) cells or patient-derived induced pluripotent stem (iPS) cells. With this objective our proposal will advance one of the focus areas of the NIH-NIDDK Beta Cell Biology Consortium, which is to use cues from pancreatic development to directly differentiate (-cells from stem/progenitor cells for use in cell-replacement therapies for diabetes. To achieve our objectives we have assembled a consortium of five investigators, which includes experts in (-cell and stem cell biology as well as genomics. By genome-wide mapping of key histone modifications in a variety of primary embryonic and adult human cells and tissues, we will define epigenetic signatures that define pancreatic progenitors and their endocrine descendants. This knowledge will be used to guide efforts for improving preexisting in vitro differentiation protocols of hES cells into pancreatic progenitors and eventually glucose-responsive insulin-producing p-cells. Key to our proposal is a novel cellular microarray technology that allows for combinatorial screening of extracellular matrix components, factors and/or molecular pathways for their ability to support efficient generation of each intermediary precursor along the step-wise differentiation path from hES cell to mature (-cell. The epigenetic signatures will be used as endpoints to assess how closely the in vitro-generated, hES cell-derived cells resemble their in vivo pancreatic counterparts. hES cell-derived (-cells will eventually be tested for their ability to correct elevated blood glucose levels upon transplantation into diabetic mouse models.