The goal of this study is to understand how epigenomic modifications in neural stem/progenitor cells contribute to the control of a dynamic balance between the state of self-renewal and differentiation, a fundamental question of developmental biology that has a direct implication for improving our understanding of the mechanisms of brain development and the possible etiology of developmental or behavioral brain disorders. This will be done by characterizing the changes of global DNA and chromatin state during neurogenesis in brain development. Our approach will be aided by the development and validation of a novel genetic strategy for isolation of endogenous neural progenitor cells. In this genetic system, neural progenitor cells and their immediate neuronal progeny are differentially marked by the expression of two reporters, thereby allowing prospective co-isolation of these two cell types and providing an endogenous source of father- daughter cells suitable for comparative genome-wide epigenetic profiling. Using this genetic system, we will purify neural progenitor cells and progeny from the developing mouse cerebral cortex, characterize differential patterns of DNA methylation and histone modification between these two cell types, identify the marks that correlate with cell type-specific expression patterns of the modified genes, and explore the potential function of these marks in the regulation of cortical neurogenesis using established in vivo functional assays. We anticipate that this study will provide a comprehensive map of the epigenetic state of neural progenitor cells during neurogenesis, identify epigenetic marks potentially crucial for neural progenitor cell fate specification, as well as help identify pathological alterations in the epigenome which may lead to developmental and behavioral brain disorders.

Public Health Relevance

Our proposed study on characterization of the epigenetic state of neural progenitor cells during the course of neurogenesis is expected to provide insight into how self-renewal and differentiation of neural progenitor cells are regulated, which has direct implication on future regenerative medicine and understanding of tumor development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094599-03
Application #
8450219
Study Section
Special Emphasis Panel (ZMH1-ERB-M (02))
Program Officer
Panchision, David M
Project Start
2011-06-15
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$403,200
Indirect Cost
$163,200
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Hahn, Maria A; Qiu, Runxiang; Wu, Xiwei et al. (2013) Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis. Cell Rep 3:291-300