Epigenetic mechanisms of gene regulation contribute significantly to normal development and disease pathogenesis. Our long-term goal is to understand the epigenetic mechanisms involved in stem cell fate choice, using the development of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) as our model. Since HSCs can be derived in vitro by directed differentiation of embryonic stem cells (ESCs), this procedure holds great promise for cell-based therapy of hematological disorders. However, compared to later stages of HSC differentiation that give rise to various blood cell lineages, epigenetic mechanisms controlling HSC fate specification from ESCs are poorly understood, impeding efforts to develop an efficient protocol for in vitro derivation of HSCs. Our preliminary data suggest that dynamic and combinatorial chromatin modifications are critical to this process. This application seeks to obtain a systems-level understanding of epigenetic regulation of HSC fate by coupling wet-lab experiments with computational modeling. Specifically, we propose to understand the dynamic and gene network aspects of epigenetic regulation. To this end, we hypothesize that dynamic combination of chromatin modifications modulates the expression of key regulators of HSC development. First, we will map genome-wide chromatin modifications at different stages of the ESC-to-HSC transition. Second, using computational tools developed in our lab and chromatin state maps, we will predict and experimentally validate regulatory DNA elements acting at different stages of the developmental process. Finally, we will develop a novel computational tool for integrating chromatin state maps with other genomics data to uncover gene pathways controlling HSC fate choice. We believe that these systems-level studies will reveal the basic principles of epigenetic regulation in development. Further, the specific knowledge of epigenetic regulation in HSCs will fill a critical knowledge gap in HSC fate specification.

Public Health Relevance

Embryonic stem cells (ESCs) hold great promise for regenerative medicine because of its ability to give rise to all tissue-specific stem cells in the human body. To fulfill this promise, accurate and efficient protocols are needed to differentiate ESCs to tissue-specific stem cells, such as hematopoietic stem cells. A better understanding of the epigenetic mechanisms governing stem cell fate choice will allow us to develop improved differentiation protocols for the generation of tissue-specific stem cells from ESCs.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG006130-03
Application #
8726458
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Pazin, Michael J
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Li, Yan; Gao, Long; Hadland, Brandon et al. (2017) CD27 marks murine embryonic hematopoietic stem cells and type II prehematopoietic stem cells. Blood 130:372-376
Yu, Wenbao; He, Bing; Tan, Kai (2017) Identifying topologically associating domains and subdomains by Gaussian Mixture model And Proportion test. Nat Commun 8:535
Li, Fengyin; He, Bing; Ma, Xiaoke et al. (2017) Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1. Cell Stem Cell 21:359-373.e5
Tober, Joanna; Maijenburg, Marijke M W; Li, Yan et al. (2017) Maturation of hematopoietic stem cells from prehematopoietic stem cells is accompanied by up-regulation of PD-L1. J Exp Med :
He, Bing; Xing, Shaojun; Chen, Changya et al. (2016) CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. Immunity 45:1341-1354
Gao, Tianshun; He, Bing; Liu, Sheng et al. (2016) EnhancerAtlas: a resource for enhancer annotation and analysis in 105 human cell/tissue types. Bioinformatics 32:3543-3551
Holmfeldt, Per; Ganuza, Miguel; Marathe, Himangi et al. (2016) Functional screen identifies regulators of murine hematopoietic stem cell repopulation. J Exp Med 213:433-49
He, Bing; Tan, Kai (2016) Understanding transcriptional regulatory networks using computational models. Curr Opin Genet Dev 37:101-108
Huang, Jianfei; Wang, Kai; Wei, Peng et al. (2016) FLAGS: A Flexible and Adaptive Association Test for Gene Sets Using Summary Statistics. Genetics 202:919-29
Ma, Xiaoke; Gao, Long; Karamanlidis, Georgios et al. (2015) Revealing Pathway Dynamics in Heart Diseases by Analyzing Multiple Differential Networks. PLoS Comput Biol 11:e1004332

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