The human embryonic stem cells (hESCs) are a unique model system for investigating the mechanisms of human development due to their ability to replicate indefinitely while retaining the capacity to differentiate into a host of functionally distinct cell types. In addition, these cells could be potentially used as therapeutic agents in regenerative medicine. Differentiation of hESCs involves selective activation or silencing of genes, a process controlled in part by the epigenetic state of the cell. In order to gain a better understanding of the epigenetic mechanisms regulating differentiation of hESCs, and produce general reference epigenome maps of the human cells, we propose to establish an Epigenome Center in San Diego. Our center will be focused on both undifferentiated hESC and four hESC-derived early embryonic cell lineages including extraembryonic endoderm, trophoblast, mesendoderm (a common precursor to mesodermal and endodermal lineages), and mesenchymal cells (a specific mesoderm derivative). We have developed and validated high throughput technologies for mapping the state of DNA methylation and chromatin modifications throughout the genome, and will use these methods to generate high-resolution maps of the reference epigenomes. Specifically, we will grow and differentiate hESCs into multiple lineages, and map DNA methylation sites using a newly developed technology that combines bisulfite conversion and whole genome shotgun sequencing. We will also determine the histone modification status in the genome by performing both ChlP-chip and ChlP-Seq analysis. We will develop advanced statistical and algorithmic solutions to facilitate high-throughput sequencing data analysis, and establish an informatics pipeline for collecting, storage, and distribution of epigenome maps. Finally, we will perform integrated data analysis to identify new epigenetic patterns in the genome that could provide insights in mechanisms of epigenetic regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01ES017166-05S2
Application #
8734633
Study Section
Special Emphasis Panel (ZRG1-CB-P (50))
Program Officer
Tyson, Frederick L
Project Start
2008-09-29
Project End
2014-06-30
Budget Start
2013-09-23
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$152,178
Indirect Cost
$52,178
Name
Ludwig Institute for Cancer Research Ltd
Department
Type
DUNS #
627922248
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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