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.
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.
|Rahl, Peter B; Young, Richard A (2014) MYC and transcription elongation. Cold Spring Harb Perspect Med 4:a020990|
|Dowen, Jill M; Young, Richard A (2014) SMC complexes link gene expression and genome architecture. Curr Opin Genet Dev 25:131-7|
|Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20|
|Chudnovsky, Yakov; Kim, Dohoon; Zheng, Siyuan et al. (2014) ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. Cell Rep 6:313-24|
|Cassady, John P; D'Alessio, Ana C; Sarkar, Sovan et al. (2014) Direct lineage conversion of adult mouse liver cells and B lymphocytes to neural stem cells. Stem Cell Reports 3:948-56|
|Anders, Lars; Guenther, Matthew G; Qi, Jun et al. (2014) Genome-wide localization of small molecules. Nat Biotechnol 32:92-6|
|Dowen, Jill M; Fan, Zi Peng; Hnisz, Denes et al. (2014) Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159:374-87|
|Arbab, Mandana; Mahony, Shaun; Cho, Hyunjii et al. (2013) A multi-parametric flow cytometric assay to analyze DNA-protein interactions. Nucleic Acids Res 41:e38|
|Whyte, Warren A; Orlando, David A; Hnisz, Denes et al. (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307-19|
|Hnisz, Denes; Abraham, Brian J; Lee, Tong Ihn et al. (2013) Super-enhancers in the control of cell identity and disease. Cell 155:934-47|
Showing the most recent 10 out of 66 publications