Mammalian organs are built of a variety of intermingled cell types, the full extent and diversity of which are unknown. Specification and maintenance of cell identity, from a single cell embryo to any terminally differentiated cell such as an adult neuron, rely heavily on epigenetic mechanisms that act upon the genome to enable or prevent expression of specific sets of genes. In doing so, epigenetic regulation of gene expression enables a single genome to encode a diverse array of cell types in a multicellular organism. Epigenetic modifications ensure that a cell proceeds through a limited set of gene expression possibilities, and once differentiated, that a cell maintains its phenotype throughout its lifetime. As a consequence, disruption of epigenetic modification can result in a variety of diseases, including neurodevelopmental and psychiatric diseases, and cancer. We propose to develop a set of mouse transgenic tools that have the potential to transform the way epigenetic modifications can be studied and understood in this mammalian model system. The new tools will provide regulated expression of epigenetic modifiers in a variety of cell types and their progenitors, while permanently marking these cells or their progeny for examination at any later time point. Moreover, we will develop technology, in which a single locus in the mouse genome can be subjected to epigenetic perturbations in specific cells and at specific times in the animal's life. We will employ these tools to gain understanding of cell-type identity in the cortex as well as the mechanisms responsible for generating and maintaining this identity. Epigenetic regulators have been implicated in a number of brain diseases, and the tools we are developing will facilitate modeling or testing specific hypotheses that relate to perturbations of epigenetic phenomena. The insights gained may also provide guidance for the generation of specific cell types in vitro, and directions for 'repurposing'certain cell types in vivo. Although the focus of ur studies will be on the mouse brain, the versatile and modular design of our tools will enable their use in studying development, function or disease in any other tissue or cell type. We will ensure easy access to all tools we generate to maximize their impact on understanding various aspects of mammalian biology.

Public Health Relevance

Epigenetic mechanisms help to ensure that each cell in a multicellular organism expresses specific genes and performs specific and appropriate functions. We are building genetic tools that will enable manipulation of epigenetic phenomena with greatly enhanced precision in the mouse brain and beyond. These approaches will have widespread impact on understanding cell identity and how it goes awry in diseases, including neurodevelopmental and psychiatric diseases, and cancer.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1-BST-N (50))
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Satterlee, John S
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Allen Institute for Brain Science
United States
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Daigle, Tanya L; Madisen, Linda; Hage, Travis A et al. (2018) A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell-Type Targeting and Functionality. Cell 174:465-480.e22
Gray, Lucas T; Yao, Zizhen; Nguyen, Thuc Nghi et al. (2017) Layer-specific chromatin accessibility landscapes reveal regulatory networks in adult mouse visual cortex. Elife 6: