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.
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., Research Associate
Makiko I. Doi, Ph.D., Postdoctoral Associate
Jonathan Lerner, Postdoctoral Associate
Ryan McCarthy, Postdoctoral Associate
Gregory Donahue, M.Sc., Computational Biologist
Dario Nicetto, Postdoctoral Associate
Jessica Grindheim, Graduate Student
Kate Palozola, Graduate Student
Meilin Fernandez Garcia, Rotation Student
Kelsey Kaeding, Rotation Student
Katherine Palozola, Graduate Student
Naomi Takenaka, Research Specialist
Ann O'Brien Jenkins, Research Specialist
Iwafuchi-Doi Makiko, Donahue Greg, Kakumanu Akshay, Watts Jason A, Mahony Shaun, Pugh B Franklin, Lee Dolim, Kaestner Klaus H, Zaret Kenneth S: The Pioneer Transcription Factor FoxA Maintains an Accessible Nucleosome Configuration at Enhancers for Tissue-Specific Gene Activation. Molecular cell 62(1): 79-91, Apr 2016.
Becker Justin S, Nicetto Dario, Zaret Kenneth S: H3K9me3-Dependent Heterochromatin: Barrier to Cell Fate Changes. Trends in genetics : TIG 32(1): 29-41, Jan 2016.
Bhat Neha, Park Jeehye, Zoghbi Huda Y, Arthur J Simon C, Zaret Kenneth S: The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development. PloS one 11(12): e0166703, 2016.
Soufi Abdenour, Garcia Meilin Fernandez, Jaroszewicz Artur, Osman Nebiyu, Pellegrini Matteo, Zaret Kenneth S: Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161(3): 555-68, Apr 2015.
Kim Jungsun, Zaret Kenneth S: Reprogramming of human cancer cells to pluripotency for models of cancer progression. The EMBO journal 34(6): 739-47, Mar 2015.
Iwafuchi-Doi Makiko, Zaret Kenneth S: Pioneer transcription factors in cell reprogramming. Genes & development 28(24): 2679-92, Dec 2014.
Xu Cheng-Ran, Li Lin-Chen, Donahue Greg, Ying Lei, Zhang Yu-Wei, Gadue Paul, Zaret Kenneth S: Dynamics of genomic H3K27me3 domains and role of EZH2 during pancreatic endocrine specification. The EMBO journal 33(19): 2157-70, Oct 2014.
Xu,C.R., Li, L.C., Donahue, G., Ying, L., Zhang, Y.W., Gadue, P., Zaret, K.S.: Dynamics of genomic H3K27me3 domains and role of EZH2 during pancreatic endocrine specification. EMBO Journal August 2014.
Bhatia Sangeeta N, Underhill Gregory H, Zaret Kenneth S, Fox Ira J: Cell and tissue engineering for liver disease. Science translational medicine 6(245): 245sr2, Jul 2014.
Metzger, D.E., Liu, C., Ziaie, A.S., Naji, A., Zaret, K.S.: Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic β-cells while repressing α-cell functions. Diabetes 63(5): 1804-1816, May 2014.
back to top
Last updated: 06/04/2019
The Trustees of the University of Pennsylvania