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 #
5P01GM099134-04
Application #
8710265
Study Section
Special Emphasis Panel (ZGM1-GDB-8)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$340,347
Indirect Cost
$98,502
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Traller, Jesse C; Cokus, Shawn J; Lopez, David A et al. (2016) Genome and methylome of the oleaginous diatom Cyclotella cryptica reveal genetic flexibility toward a high lipid phenotype. Biotechnol Biofuels 9:258
Zaret, Kenneth S; Lerner, Jonathan; Iwafuchi-Doi, Makiko (2016) Chromatin Scanning by Dynamic Binding of Pioneer Factors. Mol Cell 62:665-7
Germanguz, I; Listgarten, J; Cinkornpumin, J et al. (2016) Identifying gene expression modules that define human cell fates. Stem Cell Res 16:712-24
Becker, Justin S; Nicetto, Dario; Zaret, Kenneth S (2016) H3K9me3-Dependent Heterochromatin: Barrier to Cell Fate Changes. Trends Genet 32:29-41
White, Andrew; Flores, Aimee; Ong, Jessica et al. (2016) Hmga2 is dispensable for cutaneous squamous cell carcinoma. Exp Dermatol 25:409-12
Famenini, Sam; Rigali, Elizabeth A; Olivera-Perez, Henry M et al. (2016) Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation. FASEB J :
Zaret, Kenneth S; Mango, Susan E (2016) Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr Opin Genet Dev 37:76-81
Patel, Sanjeet; Bonora, Giancarlo; Sahakyan, Anna et al. (2016) Human Embryonic Stem Cells Do Not Change Their X Inactivation Status during Differentiation. Cell Rep :
Pastor, William A; Chen, Di; Liu, Wanlu et al. (2016) Naive Human Pluripotent Cells Feature a Methylation Landscape Devoid of Blastocyst or Germline Memory. Cell Stem Cell 18:323-9
Gu, Wen; Gaeta, Xavier; Sahakyan, Anna et al. (2016) Glycolytic Metabolism Plays a Functional Role in Regulating Human Pluripotent Stem Cell State. Cell Stem Cell 19:476-490

Showing the most recent 10 out of 41 publications