Mammalian gene regulation
chromatin, gene regulation, transcription, differentiation, liver and pancreas development.
Description of Research
The goal of the laboratory is to understand how genes are activated and different cell types are specified in embryonic development. These processes involve regulatory mechanisms that are used later in life to maintain human health, to respond to tissue damage, and during the initiation of cancers and other human diseases. The laboratory has two general approaches. First, we investigate the molecular signaling pathways that commit an undifferentiated embryonic cell, the endoderm, to a particular cell type fate, using the specification of liver and pancreas cells as a model. In the past year, we developed a fate map of the foregut endoderm in the mouse embryo, we discovered how a gene regulatory protein controls morphogenesis so that endoderm cells are properly positioned to receive organ-inductive signals, and we found distinct roles for blood vessel cells in promoting the growth of liver and pancreatic tissues at the earliest stages of organ development. The second approach of the laboratory is to investigate ways that gene regulatory proteins control the packaging of DNA in the cell nucleus, to control gene activity. Biochemical studies revealed that the regulatory protein FoxA possesses a protein segment that interacts with chromosome structural proteins, or histones, and is necessary for exposing genes sequences in chromosomes that are otherwise hidden by the histone proteins. Understanding how regulatory proteins and cell signals control gene activity and cell type decisions in development will help guide future efforts to control the differentiation and function of cells at will.
Rotation Projects for 2009-2011
1. Biochemical and genetic analysis of cell signaling and transcription factor activation in mouse embryo tissues, during liver and pancreas cell specification.
2. Epigenetic regulation of developmental gene expression.
3. Mechanisms of transcription factor modulation of chromatin structure.
4. Genetic lineage tracing of different liver and pancreas progenitors.
5. Basis for pluripotency reprogramming by transcription factor.
Jungsun Kim, Ph.D., Postdoctoral Associate
Abdenour Soufi, Ph.D., Postdoctoral Associate
Makiko I. Doi, Ph.D., Postdoctoral Associate
Gregory Donahue, M.Sc., Data Analyst
Neha Bhat, Postdoctoral Associate
Dario Nicetto, Postdoctoral Associate
Jessica Grindheim, Graduate Student
Kate Palozola, Graduate Student
Justin Becker, Rotation Student
Meilin Fernandez Garcia, Rotation Student
Tarah Brubaker, Research Specialist
Caravaca, J.M., Donahue, G., Becker, J.S., He, X., Vinson, C., Zaret, K.S.: Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes & Development 27: 251-260, February 2013.
Kim, J., Hoffman, J.P., Alpaugh, R.K., Rhim, A.D., Reichert, M., Stanger, B.Z., Furth, E.E., Sepulveda, A.R., Yuan, C.X., Won, K.J., Donahue, G., Sands, J., Gumbs, A.A., Zaret, K.S.: An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep. 3(6): 2088-2099, June 2013.
Soufi, A., Donahue, G., Zaret, K.S.: Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell 151(6): 994-1004, November 2012.
Metzger, D.E., Gasperowicz, M., Otto, F., Cross, J.C., Gradwohl, G., and Zaret, K.S.: The transcriptional corepressor Grg3/TLE3 promotes pancreatic endocrine progenitor delamination and beta-cell differentiation. Development 139: 1447-1456, April 2012.
K.S. Zaret, J.M. Caravaca, A. Tulin, and T. Sekiya: Nuclear Mobility and Mitotic Chromosome Binding: Similarities between Pioneer Transcription Factor Fox A and Linker Histone H1. Cold Spring Harbor Symposia on Quantitative Biology, Cold Spring Harbor Laboratory Press 75, April 2011.
Xu Cheng-Ran, Cole Philip A, Meyers David J, Kormish Jay, Dent Sharon, Zaret Kenneth S: Chromatin "prepattern" and histone modifiers in a fate choice for liver and pancreas. Science (New York, N.Y.) 332(6032): 963-6, May 2011.
K.S. Zaret and J.S. Carroll: Pioneer transcription factors: establishing competence for gene expression. Genes and Development 25: 2227-2241, November 2011.
Watts, J.A., Zhang, C, Kormish, J.D., Klein-Szanto, A., Zhang, M.Q., and Zaret, K.S.: Study of FoxA Pioneer Factor at Silent Genes Reveals Rfx-Repressed Enhancer at Cdx2 and a Potential Indicator of Esophageal Adenocarcinoma Development. PLoS Genetics 7(E1002277), 2011.
Sekiya, T., Muthurajan, U.M., Tulin, A., McPherson, C., Luger, K., and Zaret, K.S.: Nucleosome-binding affinity as a primary determinant of the nuclear mobility of pioneer transcription factor FoxA. Genes and Development 23: 804-809, 2009.
Zaret Kenneth S, Grompe Markus: Generation and regeneration of cells of the liver and pancreas. Science (New York, N.Y.) 322(5907): 1490-4, Dec 2008.
Zaret KS, Watts J, Xu J, Wandzioch E, Smale ST, Sekiya T: Pioneer Factors, Genetic Competence, and Inductive Signaling: Programming Liver and Pancreas Progenitors from the Endoderm. Cold Spring Harbor symposia on quantitative biology Nov 2008.
Zaret Kenneth S: Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nature reviews. Genetics 9(5): 329-40, May 2008.
Sekiya Takashi, Zaret Kenneth S: Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo. Molecular cell 28(2): 291-303, Oct 2007.
Wandzioch, E., and Zaret, K.S.: Dynamic Signaling network for the specification of embryonic pancreas and liver progenitors. Science 324: 1707-1710, 2009.
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Last updated: 12/10/2013
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