We have described key features of the core transcriptional regulatory circuitry of human and murine embryonic stem cells (ESCs) and identified fundamental regulatory mechanisms that contribute to the control of gene expression programs in mammalian cells. Several research groups have recently discovered that master transcription factors bind large clusters of transcriptional enhancers, called super- enhancers, which drive expression of genes that play key roles in the control of transcriptional regulatory circuitry and cell identity. A substantial portion of disease-associated variation occurs in these super- enhancers. Thus, super-enhancers play important roles in the control of cellular identity in both normal and disease states. However, gaps in our understanding of super-enhancer structure and function limit our understanding their roles in control of cell state, in development and in disease. We propose to expand our understanding of the transcriptional control of mammalian cell identity by further investigating super- enhancer components and functions in ESCs and other clinically important cell types. In addition, super- enhancers suggest a new approach to investigate the regulatory circuitry of clinically important cells, and we propose to test this approach. To accomplish these goals, the specific aims of the proposal are: 1) Further investigate the structure and function of super-enhancers, 2) Determine whether the noncoding RNA produced from super-enhancers contributes to enhancer function in ESCs, 3) Investigate the dynamics of super-enhancer decommissioning and establishment during differentiation, and 4) Investigate the regulatory circuitry of clinically important cell types through super-enhancer analysis. Improved understanding of super-enhancers should continue to produce new insights into the control of cell state, reveal the key themes that operate to control gene expression programs in mammalian cell types, and produce new insights into disease mechanisms. These studies should also provide the foundation for understanding transcriptional regulation in a broad spectrum of normal and diseased cells and for cellular reprogramming of clinically important cells.

Public Health Relevance

Our research addresses the fundamental problem of how cell identity is regulated at the level of the genome. Improved understanding of transcriptional regulatory circuitry in human cells will reveal how gene expression programs are controlled and will likely produce new insights into disease mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
2R01HG002668-11A1
Application #
8760391
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Feingold, Elise A
Project Start
2003-05-02
Project End
2017-06-30
Budget Start
2014-09-22
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$969,151
Indirect Cost
$472,150
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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