Induced pluripotent stem (iPS) cells have a tremendous potential for aidvancing our understanding of human development and disease. To help unlock this potential we have organized a program to (A) comprehensively identify the genetic and epigenetic components of the regulatory network that maintains cells in a pluripotent state;(B) characterize culture-induced variation in the activites of these components in pluripotent cells;and (C) characterize temporal variation in their activities during induction of pluripotency with defined factors. To achieve these goals, we have formulated four interdependent projects: Project I (Meissner) will (1) characterize transcriptional coregulators and small non-coding RNAs that modulate the activity of the core pluripotency transcription factors, and (2) define and isolate subpopulations from pluripotent cell cultures to characterize their transcriptional and epigenetic states. Project II (Rinn) will characterize long non-coding RNAs expressed in pluripotent cells and elucidate their role in remodeling the epigenetic landscape during reprogramming. Project III (Mikkelsen) will characterize the cis-regulatory modules that direct activation, maintenace and repression of gene expression in pluripotent cells by recruiting transcription factors and their coregulators to key genomic loci. Project IV (Eggan) will characterize the inheritance patterns and maintenance of inactivated X chromosomes during reprogramming and in pluripotent cell cultures. The four projects rely on complementary use of innovative high-throughput genomic and proteomic technologies to profile high-quality iPS cell lines. The integration of data and insights from each of the projects will generate a comprehensive view of protein-protein, protein-RNA and protein-DNA interactions essential to the maintenace of pluripotency (goal A). This intergrated view will then guide studies of culture- induced and temporal variation in the network (goals B and C).

Public Health Relevance

Induced pluripotent stem cells are a potential revolutionary tool for disease modeling, drug screening and regenerative medicine. This program is organized to fully characterize the molecular properties of these cells, which is essential to ensure that their use in biomedicine is effective and safe.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM099117-03
Application #
8535278
Study Section
Special Emphasis Panel (ZGM1-GDB-8 (IP))
Program Officer
Haynes, Susan R
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$2,108,013
Indirect Cost
$606,005
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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Rinn, John; Guttman, Mitchell (2014) RNA Function. RNA and dynamic nuclear organization. Science 345:1240-1
Smith, Zachary D; Chan, Michelle M; Humm, Kathryn C et al. (2014) DNA methylation dynamics of the human preimplantation embryo. Nature 511:611-5
Lu, Yu; Loh, Yuin-Han; Li, Hu et al. (2014) Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell 15:92-101
Trapnell, Cole; Cacchiarelli, Davide; Grimsby, Jonna et al. (2014) The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol 32:381-6
Ichida, Justin K; TCW, Julia; T C W, Julia et al. (2014) Notch inhibition allows oncogene-independent generation of iPS cells. Nat Chem Biol 10:632-9
Federation, Alexander J; Bradner, James E; Meissner, Alexander (2014) The use of small molecules in somatic-cell reprogramming. Trends Cell Biol 24:179-87
Karnik, Rahul; Meissner, Alexander (2013) Browsing (Epi)genomes: a guide to data resources and epigenome browsers for stem cell researchers. Cell Stem Cell 13:14-21
Sun, Lei; Goff, Loyal A; Trapnell, Cole et al. (2013) Long noncoding RNAs regulate adipogenesis. Proc Natl Acad Sci U S A 110:3387-92
Smith, Zachary D; Meissner, Alexander (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204-20

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