The overarching theme of this Program will be to define how the cell cycle coordinates epigenetic events and chromosome remodeling and how this impacts on pluripotency and cell fate decisions. The Program comprises three highly interactive and synergistic projects built on a common biological platform, all supported by scientific cores. Project 1 will define how epigenetic regulation and chromosome architecture are subject to cell cycle control at developmentally-regulated genes. Preliminary data indicates that GI is a 'permissive'phase of the cell cycle when cells are capable of responding to differentiation signals. Experiments proposed in this Project will define a mechanism linking cell cycle transition to the activation of differentiation pathways. Project 2 will establish how PNA replication timing and global genome rearrangements impact differentiation decisions and how this is coordinated with the cell cycle. A second focus of this project will be to understand the role of Rifl in chromosome organization and cell fate decisions. Rifl is essential for establishing the correct replication timing program and is likely to have critical roles in chromosome reorganization during differentiation. Project 3 will look at how 'insulators'control chromosome organization during the cell cycle and then will investigate mechanisms by which topological domains are formed in pluripotent cells. Finally, this Project will characterize the role of insulators in genome organization as pluripotent cells differentiate. The three Projects are tightl interconnected and address overlapping biological themes with complementary approaches - this will create a high level of synergy within the Program. All Projects will heavily utilize the Stem Cell Core (Core A), the Bioinformatics Core (Core B), and will be supported by an Administrative Core (Core C). The Cores have key roles in supporting activities that would not be feasible outside the framework of a Program Project. The Program also leverages resources to increase synergy and critical mass through support of Pilot Projects and collaborations.
Pluripotent stem cells are at the forefront of a new revolution in biomedical research and serve important roles in drug screening, disease modeling and regenerative medicine. This Program is focused on the basic understanding of pluripotent stem cells so that in the future they can be more effectively and safely used in clinical applications.
|Sima, Jiao; Bartlett, Daniel A; Gordon, Molly R et al. (2018) Bacterial artificial chromosomes establish replication timing and sub-nuclear compartment de novo as extra-chromosomal vectors. Nucleic Acids Res 46:1810-1820|
|Singh, Amar M; Dalton, Stephen (2018) What Can 'Brown-ing' Do For You? Trends Endocrinol Metab 29:349-359|
|Dixon, Jesse R; Xu, Jie; Dileep, Vishnu et al. (2018) Integrative detection and analysis of structural variation in cancer genomes. Nat Genet 50:1388-1398|
|Xu, Chenhuan; Corces, Victor G (2018) Genome-Wide Mapping of Protein-DNA Interactions on Nascent Chromatin. Methods Mol Biol 1766:231-238|
|Dileep, Vishnu; Gilbert, David M (2018) Single-cell replication profiling to measure stochastic variation in mammalian replication timing. Nat Commun 9:427|
|Colunga, Thomas; Dalton, Stephen (2018) Building Blood Vessels with Vascular Progenitor Cells. Trends Mol Med 24:630-641|
|Wang, Tao; Holt, Matthew V; Young, Nicolas L (2018) The histone H4 proteoform dynamics in response to SUV4-20 inhibition reveals single molecule mechanisms of inhibitor resistance. Epigenetics Chromatin 11:29|
|Xu, Chenhuan; Corces, Victor G (2018) Nascent DNA methylome mapping reveals inheritance of hemimethylation at CTCF/cohesin sites. Science 359:1166-1170|
|Marchal, Claire; Sasaki, Takayo; Vera, Daniel et al. (2018) Genome-wide analysis of replication timing by next-generation sequencing with E/L Repli-seq. Nat Protoc 13:819-839|
|Rivera-Mulia, Juan Carlos; Schwerer, Hélène; Besnard, Emilie et al. (2018) Cellular senescence induces replication stress with almost no affect on DNA replication timing. Cell Cycle 17:1667-1681|
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