Recent evidence suggests that mouse embryonic stem cells can self-renew in different states of pluripotency, embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs), which developmentally correspond to pre- and post-implantation stage epiblast of the embryo, respectively. Exogenous expression of individual transcription factors has been shown to be sufficient to reprogram EpiSCs into na?ve ESCs. However, despite the developmental similarities of these pluripotent cell types, conversion efficiencies remain low and little is known about the underlying transcriptional, epigenetic, and signaling events of this process. In order to elucidate the mechanisms of EpiSC-to-ESC reprogramming, we here propose to (i) establish fluorescent reporter and inducible transgenic tools to effectively study this process, (ii) define intermediate stages of EpiSC-to-ESC conversion at the transcriptional and epigenetic level, and (iii) perform an unbiased genome-wide shRNA screen to identify novel roadblocks of this process. The investigation of the mechanism of EpiSC-to-ESC conversion is a powerful platform from which we can discover genes important during pre-implantation development and the acquisition of pluripotency. Moreover, we expect that our studies will provide important clues for stabilizing a na?ve pluripotent state in human cells.

Public Health Relevance

Embryonic stem cells have the potential to be harnessed for biomedical applications such as cell transplantation, disease modeling, and drug screening. Understanding the regulatory networks involved in the acquisition and maintenance of pluripotency is crucial to fulfilling this promise. To this end, the proposed research aims to characterize the mechanism of interconversion between two developmentally distinct murine pluripotent cell types.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD079225-01A1
Application #
8784669
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ravindranath, Neelakanta
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199