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Investigating regulators controlling differentiation potential of ES cells

研究控制 ES 细胞分化潜能的调节因子

基本信息

批准号：
10693165
负责人：
Jonghwan Kim
金额：
$ 32.49万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10693165
关键词：
Address Adult Affect Apoptosis Award Biomedical Research CASP3 gene Caspase Cell Death Cell Density Cell Fate Control Cell Survival Cell Therapy Cells Cessation of life Characteristics Decision Making Disease model ES Cell Line Embryo Embryonic Development Enhancers Environment Epigenetic Process Factor Analysis Foundations Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Transcription Genomics Heterogeneity In Vitro Individual Knowledge Knowledge acquisition Link Maps Mechanics Mediating Metabolic MicroRNAs Molecular Monitor National Institute of General Medical Sciences Organism Outcome Pathway interactions Pluripotent Stem Cells Population Proliferating Proteins Regulation Reporter Reproducibility Research Research Support Role Signal Pathway Signal Transduction Stem Cell Development Techniques Testing Therapeutic Tissue-Specific Gene Expression Work YY1 Transcription Factor beta catenin cell behavior cell fate specification cell type density drug discovery embryonic stem cell induced pluripotent stem cell insight instrument interest neglect novel overexpression pluripotency programs protein expression self-renewal single-cell RNA sequencing stem stem cell differentiation stem cell fate stem cell self renewal stem cell therapy stem cells tool transcription factor transcriptome

项目摘要

SUMMARY Pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells can proliferate indefinitely in vitro without changes in their characteristics (self-renewal) while keeping their potential to give rise to almost all cell types in adult organisms (pluripotency). Due to such exceptional characteristics, ES and iPS cells have been extensively studied and used as tools for understanding the molecular basis of early embryo development and also serve as useful instruments in drug discovery and establishing various disease models. To fully utilize their potential in therapeutic applications, it is crucial to completely understand how these two unique characteristics are modulated. Prior studies have largely focused on understanding of self-renewal, allowing us to better illuminate the regulatory mechanisms mediated by key transcription factors (TFs), signaling pathways, and other associated genomic features. On the other hand, understanding of exit mechanisms from self-renewal towards cell fate specification, and factors involved in proper differentiation of pluripotent stem cells have not yet been systematically examined. The long-term objective of the proposed research is to investigate regulators controlling differentiation potential of pluripotent stem cells. In our previous research supported by NIGMS awards, we have revealed multiple TFs, epigenetic regulators, and genomic features that influence the differentiation potential of ES cells. Among those factors, we showed that Yap1, a transcriptional co- regulator, downstream of the Hippo pathway, is dispensable for self-renewal but required for differentiation of ES cells. We furthermore revealed the roles of Yap1 in safeguarding ES cells from excessive cell death during differentiation. We additionally observed that cell density, tightly linked to the Hippo signaling activity, significantly affects global gene expression programs of not only self-renewing ES cells, but also their differentiation potential. However, underlying mechanisms of ES cell differentiation in the context of cell density and survival vs. death decision have been elusive. To address this critical gap in knowledge, our objectives of the proposal will be 1) to determine, at the single cell level, how the survival vs. death decision is made when ES cells differentiate, 2) to define outcomes of density- dependent gene expression signatures and enhancer usage during ES cell self-renewal and differentiation, and 3) to identify effectors controlling density-dependent gene expression programs and elucidate their regulatory mechanisms. The information obtained from the proposal will provide novel insights into the reproducibility issues in biomedical studies caused by inconsistencies in cell density between different experimental techniques. 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.

总结