The long-term goal of this grant is to reveal molecular mechanisms by which particular cell type choices are made in multipotent progenitor cells in the mammalian embryo. The research seeks to understand how extracellular signals converge on progenitor cells to induce a cell fate choice and how multipotent progenitors gain the competence to choose certain fates and be excluded from others. Since the vast majority of embryonic progenitors, adult stem cells, and perhaps cancer progenitors in the body are multipotent, not pluripotent, understanding the principles by which multipotent progenitors gain their special competencies and limitations is of fundamental biomedical importance. As a model system, we investigate the specification of liver progenitors from multipotent foregut endoderm cells in the early mouse embryo. These studies identified the concept that pioneer transcription factors help establish cell type competency by opening up local domains of chromatin at silent liver target genes in the endoderm. We hypothesize that transcription factors that convert differentiated cells to pluripotency can function as pioneer factors. Recently, we discovered co-regulators that modify chromatin architecture with FoxA pioneer factors and revealed the basis by which Fox proteins, compared to other factors, scan the genome in the living cell nucleus. In addition, we discovered a dynamic signaling network that induces the hepatic fate In multipotent endoderm, and more recently have traced the inducing signals down to the chromatin of recipient target genes. Our integrative view is enabled by our development of new cell sorting capacities from early embryos and scaled-down molecular biology and chromatin immunoprecipitation technology. Finally, we can now trace the fate and function of different types of progenitor cells in the mammalian foregut. We performed genomic expression analysis of different patches of endoderm cells and then made cre-ER transgenes driven by the differentially expressed genes. Our basic findings have been translated by many other laboratories to explain how pioneer factors enable cancer cells to be hormone responsive and to differentiate embryonic stem cells into endoderm cells and liver cells. Further work from this grant is anticipated to provide insights into the mechanisms of cell programming and the means by which different progenitor types can be programmed to particular ceil fates.

Public Health Relevance

improvements in the ability to program progenitor cells and stem cells, and to reprogram differentiated cells, will provide therapies for human diseases, allow researchers to investigate early manifestations of disease genomes. and to screen for drugs that ameliorate cellular dysfunction. To enable such possibilities, my grant investigates the normal genetic regulatory mechanisms by which mammalian cell type specification occurs, so that the efficiency of therapeutic and diagnostic cell programming can be enhanced.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Haynes, Susan R
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Bhatia, Sangeeta N; Underhill, Gregory H; Zaret, Kenneth S et al. (2014) Cell and tissue engineering for liver disease. Sci Transl Med 6:245sr2
Zaret, Kenneth S (2014) Genome reactivation after the silence in mitosis: recapitulating mechanisms of development? Dev Cell 29:132-4
Zaret, Kenneth S (2014) At the revolution with Fred Sherman. Mol Cell Biol 34:922-5
Kim, Jungsun; Hoffman, John P; Alpaugh, R Katherine et al. (2013) An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep 3:2088-99
Watts, Jason A; Zhang, Chaolin; Klein-Szanto, Andres J et al. (2011) Study of FoxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development. PLoS Genet 7:e1002277
Zaret, Kenneth S; Carroll, Jason S (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227-41
Xu, Cheng-Ran; Cole, Philip A; Meyers, David J et al. (2011) Chromatin "prepattern" and histone modifiers in a fate choice for liver and pancreas. Science 332:963-6
Santisteban, Pilar; Recacha, Pablo; Metzger, David E et al. (2010) Dynamic expression of Groucho-related genes Grg1 and Grg3 in foregut endoderm and antagonism of differentiation. Dev Dyn 239:980-6
Xu, Jian; Watts, Jason A; Pope, Scott D et al. (2009) Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev 23:2824-38
Wandzioch, Ewa; Zaret, Kenneth S (2009) Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 324:1707-10

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