Self-renewal and pluripotency are defining characteristics of stem cells common in both embryonic stem (ES) cells (derived from developing embryos) and induced pluripotent stem (iPS) cells (derived from differentiated somatic cells). These cells can self-renew for a prolonged time in vitro and retain differentiation potential (pluripotency) to give rise to all possible cell types of developing organisms. Due to such exceptional characteristics, ES and iPS cells have been studied extensively for understanding the molecular basis of early development, and serve as useful instruments in drug discovery and establishing human disease models. Since transcription factors, Oct4, Sox2, and Nanog have been identified in ES cells as playing master regulatory roles in self-renewal processes, advances in high-throughput technologies have led to the discovery of additional cofactors of master regulators. These discoveries have allowed us to better understand the regulatory mechanisms of stem cell self-renewal. On the other hand, our understanding of the regulatory mechanisms that retain the differentiation potential of stem cells is significantly limied and such mechanisms have not yet been systematically examined. Obviously, complete understanding of both self-renewal and pluripotency would be crucial in harnessing the full potential of pluripotent stem cells in future therapeutic applications. The objective of the proposed research is to better understand the regulatory mechanisms governing the differentiation potential of ES cells. Our primary questions are 1) What are the transcription factors involved in maintaining and controlling the differentiation potential of pluripotent stem cells? 2) How do they influence the direction of early lineage specification? 3) What is the nature of the regulatory networks they form, and how do these networks intertwine with the previously known self-renewal network? We will address these questions systematically by applying a signature based screening method in combination with various systems biology tools. Successful completion of this project will not only allow us to functionally characterize novel regulators controlling the differentiation potential of stem cells, but also illustrate the full viw of regulatory mechanisms governing the hallmarks of pluripotent stem cells. Furthermore, outcomes of this proposal will provide a foundation for manipulation of stem cells to control cell fates towards desired lineages, and contribute to the advances in stem cell based cell therapies.

Public Health Relevance

The knowledge acquired from the proposed research will expand our understanding of the distinct characteristics of pluripotent stem cells, especially factors that alter differentiation potential of stem cells, which will be enormously important in future therapeutic applications. The information will provide a foundation for manipulation of stem cells to control cell fates towards desired lineages, and contribute to the advances in development of stem cell based cell therapies using ES cells and/or iPS cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM112722-04
Application #
9552876
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Gibbs, Kenneth D
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
Lee, Bum-Kyu; Uprety, Nadima; Jang, Yu Jin et al. (2018) Fosl1 overexpression directly activates trophoblast-specific gene expression programs in embryonic stem cells. Stem Cell Res 26:95-102
LeBlanc, Lucy; Lee, Bum-Kyu; Yu, Andy C et al. (2018) Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation. Elife 7:
Beck, Samuel; Rhee, Catherine; Song, Jawon et al. (2018) Implications of CpG islands on chromosomal architectures and modes of global gene regulation. Nucleic Acids Res 46:4382-4391
Lee, Bum-Kyu; Lee, Jiwoon; Shen, Wenwen et al. (2017) Fbxl19 recruitment to CpG islands is required for Rnf20-mediated H2B mono-ubiquitination. Nucleic Acids Res 45:7151-7166
Rhee, Catherine; Edwards, Melissa; Dang, Christine et al. (2017) ARID3A is required for mammalian placenta development. Dev Biol 422:83-91
Rhee, Catherine; Kim, Jonghwan; Tucker, Haley O (2017) Transcriptional Regulation of the First Cell Fate Decision. J Dev Biol Regen Med 1:
Rhee, Catherine; Lee, Bum-Kyu; Beck, Samuel et al. (2017) Mechanisms of transcription factor-mediated direct reprogramming of mouse embryonic stem cells to trophoblast stem-like cells. Nucleic Acids Res 45:10103-10114
Skamagki, Maria; Correia, Cristina; Yeung, Percy et al. (2017) ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors. Nat Cell Biol 19:1037-1048
Chung, HaeWon; Lee, Bum-Kyu; Uprety, Nadima et al. (2016) Yap1 is dispensable for self-renewal but required for proper differentiation of mouse embryonic stem (ES) cells. EMBO Rep 17:519-29