Development of the central nervous system requires orchestrated interactions among several regulatory elements that determine the fate, properties, and functions of cells at any given time, ultimately leading to complex neural networks that control our most basic behaviors and complex cognitive processes. As an intermediate regulatory domain between DNA sequences and gene expression, epigenetic mechanisms can exert considerable influence on brain development on a scale that we are only beginning to appreciate. One major advance in the field of epigenetics in recent years is the discovery of novel modifications of genomic DNA, such as 5-hydroxymethylcytosine (5hmC), and molecular pathways to install, remove, and interpret these modifications, which are highly enriched in the nervous system and are dynamically regulated by neuronal activity under physiological and pathological conditions. The overarching goal of this P01 is to take a systematic approach to understand how global and specific changes in the epigenome and transcriptome regulate stem cell behavior, neuronal development and neuronal integration using hippocampal neurogenesis as a model system. Hippocampal neurogenesis is a constitutive phenomenon in the adult mammalian brain and is a well- established model for neural development that is comprised of defined stages, which originate with neural stem cell activation and result in the maturation and integration of a single neuronal subtype in an anatomically restricted region of the brain. This phenomenon also represents striking structural plasticity and has been shown to contribute to critical brain functions, whereas its dysregulation has been implicated in various neurological and degenerative disorders. Characterization of neurogenic processes in hippocampus may eventually inform cell transplantation-based therapeutic strategies to repair the central nervous system after stroke, injury or neurological disorders. Integrating results from adult hippocampal neurogenesis in rodents with human induced pluripotent stem cell (iPSC)-based models will allow for the identification of fundamental epigenetic principles governing neural development at the molecular, cellular, and systems levels. Our team includes experts in epigenetics, hippocampal neurogenesis, rodent stem cell biology, human iPSCs, chemical biology, high-throughput sequencing, bioinformatics, electrophysiology and transplantation. Successful completion of the research projects will guide future investigations into the role of dysregulated DNA modifications in neurodevelopmental disorders and facilitate the development of new technological approaches to identify epigenetic marks with high resolution.

Public Health Relevance

Understanding the epigenetic mechanisms underlying neurogenesis can have far-reaching implications for numerous fields including basic stem cell biology, neurodevelopmental disorders, and future therapeutic strategies for neural repair based on transplantation. This program is a collaborative effort among leaders in neural development, neuroepigenetics, structural biology, novel next generation sequencing and human induced pluripotent stem cells to investigate how epigenetic modifications regulate the entire process of neurogenesis in both animal models and human cellular systems.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1)
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Lavaute, Timothy M
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University of Pennsylvania
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