The promise of stem cell biology is predicated on the idea that these cells will be utilized in regenerative medicine and to model development and disease of tissues in vitro. While fantastic progress has been made in the generation of patient-specific stem cells through the use of reprogramming of somatic cells to a pluripotent state, little is known about the basic biology of these cells and whether they will be able to live up to their promise in regenerative medicine, development and disease. We have found that in vitro differentiation from hESCs and hiPSCs does not accurately reflect in vivo differentiation in human tissue. We have identified a molecular basis for this discrepancy and preliminary data suggest that in fact differentiation from human pluripotent stem cells could reflect human development but from a very early embryonic stage. We identified LIN28/let-7 as able to control human differentiation during early fetal development, in congruence with what has been shown for this circuit in C. Elegans. We propose to manipulate this important gene expression circuit to determine whether proper control of this circuit is vital to allow for maturation of human cells. This project will also develop tools that will allow for manipulation of this circuit and a simplified method for driving cellular maturation in vitro. Finally, we will use genome-wide approaches to understand how this circuit is normally regulated and whether it is representative of a cohort of co-regulated genes important for human development. This project will significantly contribute to our limited knowledge of human development, and the control of cell fate with human pluripotent stem cells. There will be no human subjects or animal experimentation with the proposed work.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM099134-03
Application #
8520351
Study Section
Special Emphasis Panel (ZGM1-GDB-8)
Project Start
2013-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$329,087
Indirect Cost
$95,573
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Soufi, Abdenour (2014) Mechanisms for enhancing cellular reprogramming. Curr Opin Genet Dev 25:101-9
Patterson, M; Gaeta, X; Loo, K et al. (2014) let-7 miRNAs can act through notch to regulate human gliogenesis. Stem Cell Reports 3:758-73
Pasque, Vincent; Tchieu, Jason; Karnik, Rahul et al. (2014) X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency. Cell 159:1681-97
Smale, Stephen T (2014) Transcriptional regulation in the immune system: a status report. Trends Immunol 35:190-4
Sridharan, Rupa; Gonzales-Cope, Michelle; Chronis, Constantinos et al. (2013) Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1? in reprogramming to pluripotency. Nat Cell Biol 15:872-82
Minkovsky, Alissa; Barakat, Tahsin Stefan; Sellami, Nadia et al. (2013) The pluripotency factor-bound intron 1 of Xist is dispensable for X chromosome inactivation and reactivation in vitro and in vivo. Cell Rep 3:905-18
Papp, Bernadett; Plath, Kathrin (2013) Epigenetics of reprogramming to induced pluripotency. Cell 152:1324-43
Denholtz, Matthew; Bonora, Giancarlo; Chronis, Constantinos et al. (2013) Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. Cell Stem Cell 13:602-16
Ho, Ritchie; Papp, Bernadett; Hoffman, Jackson A et al. (2013) Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. Cell Rep 3:2113-26

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