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 #
5U01ES017166-05
Application #
8311845
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
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$3,218,417
Indirect Cost
$546,593
Name
Ludwig Institute for Cancer Research Ltd
Department
Type
DUNS #
627922248
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zhu, Yun; Chen, Zhao; Zhang, Kai et al. (2016) Constructing 3D interaction maps from 1D epigenomes. Nat Commun 7:10812
Hou, Zhonggang; Meyer, Susanne; Propson, Nicholas E et al. (2015) Characterization and target identification of a DNA aptamer that labels pluripotent stem cells. Cell Res 25:390-3
Schultz, Matthew D; He, Yupeng; Whitaker, John W et al. (2015) Human body epigenome maps reveal noncanonical DNA methylation variation. Nature 523:212-6
Whitaker, John W; Nguyen, Tung T; Zhu, Yun et al. (2015) Computational schemes for the prediction and annotation of enhancers from epigenomic assays. Methods 72:86-94
Pugacheva, Elena M; Rivero-Hinojosa, Samuel; Espinoza, Celso A et al. (2015) Comparative analyses of CTCF and BORIS occupancies uncover two distinct classes of CTCF binding genomic regions. Genome Biol 16:161
Leung, Danny; Jung, Inkyung; Rajagopal, Nisha et al. (2015) Integrative analysis of haplotype-resolved epigenomes across human tissues. Nature 518:350-4
Whitaker, John W; Chen, Zhao; Wang, Wei (2015) Predicting the human epigenome from DNA motifs. Nat Methods 12:265-72, 7 p following 272
Huo, Wenwen; Adams, Hannah M; Zhang, Michael Q et al. (2015) Genome Modification in Enterococcus faecalis OG1RF Assessed by Bisulfite Sequencing and Single-Molecule Real-Time Sequencing. J Bacteriol 197:1939-51
Wang, Allen; Yue, Feng; Li, Yan et al. (2015) Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates. Cell Stem Cell 16:386-99
Dixon, Jesse R; Jung, Inkyung; Selvaraj, Siddarth et al. (2015) Chromatin architecture reorganization during stem cell differentiation. Nature 518:331-6

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