題目：Deconstructing endodermal organ development to reconstruct organs from stem cells
講座人：Maike Sander, M.D.
Department of Pediatrics and Cellular & Molecular Medicine
Director, Pediatric Diabetes Research Center
Sanford Consortium for Regenerative Medicine
University of California, San Diego
Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To gain a comprehensive understanding of how signals are translated into transcriptional changes during developmental progression, we generated genome-scale maps of gene transcription, transcription factor occupancy, chromatin modifications, and 3D chromatin during the stepwise differentiation of human pluripotent stem cells (hPSCs) toward the pancreatic lineage. Building upon these maps, we investigated epigenetic mechanisms of gene activation and gene silencing associated with organ lineage commitment and cell differentiation. We found that chromatin patterns are highly informative for identifying functionally related genes and that epigenetic information facilitates the identification of novel regulators of developmental transitions. We further observed that binding of specific transcription factors serves as a predictor for the cell’s ability to respond to extrinsic differentiation cues. Through manipulation of transcription factors and chromatin modifiers during develpomental progression, our work has provided insight into cell-intrinsic epigenetic mechanisms that modify signal-induced transcriptional responses. These findings have implications for the design of directed differentiation and reprogramming strategies to produce functional endodermal organ cell types in vitro.