Embryonic stem (ES) and induced pluripotent stem (iPS) cells hold enormous potential for diverse medical applications, limited primarily by our methods to direct the activities of these cells toward specific therapeutic goals. A more complete understanding of the regulatory circuitry of pluripotent stem cells would almost certainly provide insights useful to overcome this limitation. We propose to expand knowledge of the transcriptional regulatory circuitry of murine and human embryonic stem (ES) cells by identifying novel ES cell transcription factors, chromatin regulators and signaling proteins and by determining how they function together to control the gene expression program responsible for pluripotency and self-renewal. Furthermore, we propose to use improved understanding of the control of ES cell state to develop more powerful methods for cellular reprogramming to generate iPS cells. To accomplish these goals, the specific aims of the proposal are: 1) Combine and further develop powerful experimental and analytical technologies that can identify novel regulators of ES cell state and determine their genome-wide occupancy and function;2) Identify novel transcription factors, chromatin regulators and signaling proteins that play key roles in murine and human ES cell identity;3) Determine how novel transcription factors, chromatin regulators and signaling proteins contribute to pluripotency and self-renewal in murine and human ES cells;and 4) Use cellular reprogramming assays to gain insights into the control of cell state and to develop more powerful methods for cellular reprogramming. Improved understanding of transcriptional regulatory circuitry from these studies will lead to new insights into the control of ES cell state, reveal how key regulators control the gene expression program of ES cells, facilitate efforts to manipulate cell fates for regenerative medicine, and provide the foundation for further mapping regulatory circuitry in human and other vertebrate cells.

Public Health Relevance

We plan to expand knowledge of the regulatory circuitry of embryonic stem cells by identifying novel ES cell regulators and determining how they function to control the gene expression program that is unique to these pluripotent cells. Embryonic stem cells hold enormous potential for diverse medical applications and improved understanding of regulatory circuitry from these studies should facilitate efforts to manipulate cell fates for regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
3R01HG002668-10S1
Application #
8824724
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Feingold, Elise A
Project Start
2003-05-02
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$311,351
Indirect Cost
$151,684
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M et al. (2016) Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol 12:876-84
Ji, Xiong; Dadon, Daniel B; Powell, Benjamin E et al. (2016) 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell 18:262-75
Kaufman, Charles K; Mosimann, Christian; Fan, Zi Peng et al. (2016) A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science 351:aad2197
Hnisz, Denes; Weintraub, Abraham S; Day, Daniel S et al. (2016) Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351:1454-8
Liu, X Shawn; Wu, Hao; Ji, Xiong et al. (2016) Editing DNA Methylation in the Mammalian Genome. Cell 167:233-247.e17
Saint-André, Violaine; Federation, Alexander J; Lin, Charles Y et al. (2016) Models of human core transcriptional regulatory circuitries. Genome Res 26:385-96
Heyn, Holger; Vidal, Enrique; Ferreira, Humberto J et al. (2016) Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol 17:11
Hnisz, Denes; Day, Daniel S; Young, Richard A (2016) Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control. Cell 167:1188-1200
Mannini, Linda; C Lamaze, Fabien; Cucco, Francesco et al. (2015) Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome. Sci Rep 5:16803
Hnisz, Denes; Schuijers, Jurian; Lin, Charles Y et al. (2015) Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell 58:362-70

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