Genomics of definitive endoderm, Cellular differentiation, hESCs
Cellular differentiation is governed by dynamic changes occurring in the genome. We are interested in how these mechanisms – including epigenetic marks, changes in chromatin structure and gene expression - are used by the genome to instruct the very first differentiation events in the embryo. These differentiation events begin when the blastocyst becomes fated toward either embryonic or extraembryonic tissues and then continue upon the beginning of the first germ layers: endoderm, ectoderm and mesoderm. To understand these dramatic early events, we have developed human embryonic stem cells as a model system. We are able to differentiate hESCs into definitive endoderm, trophoblast and ectoderm and are developing new ways to derive hESCs from human blastocysts which are free from animal contaminants and more karyotypically stable than those currently available. To date our major contribution has been in the study of endoderm and trophoblast cells, either in whole embryos using expression cloning or microarray analysis or in hESC differentiated toward these lineages. More recently, we have made significant progress in using novel genomic tools, including high throughput sequencing to elucidate methylation patterns, chromatin structure and transcriptional differences between naïve hESC and definitive endoderm derived from hESCs. Furthermore, we have performed an extensive analysis on the regulation of the transcriptome throughout embryogenesis in both the embryonic and extraembryonic lineages and are currently using these comprehensive datasets to understand gene regulation during organogenesis and gastrulation in the mouse. Using this data we have made inroads into understanding placental morphogenesis and the evolution of this novel organ (Knox and Baker; Mitiku and Baker). Our goals for the future are to use the genomic information obtained from these early differentiation events to inform the eventual creation of new tissues for therapeutics.