This Project will define the mechanisms by which human embryonic stem cell (hESC) self-renewal is preserved and how early differentiation decisions are made. These studies focus on the role of PI3K in promoting GSK3-beta activity, a point of regulation that is critical for blocking an epithelial to mesenchymal transition (EMT) and differentiation towards mesendoderm. Control of mesendoderm development, following loss of PI3K and GSK3-beta activity, is not well understood. To address this issue, respective roles for Wnt and TGF-beta family members in mesendoderm specification will be defined. Understanding these issues is critical not only in relation to hESC self-renewal, but also for understanding the basic mechanisms underpinning early cell fate decisions, including definitive endoderm and mesoderm specification from a mesendoderm precursor.
The first Aim of this Project will investigate the role of GSK3-beta in control of EMTs and how it regulates the activity of two transcription factors, Snail 1 and beta-catenin. Mechanisms by which these transcription factors control EMTs will be defined.
The second Aim will investigate the signaling pathways required for hESC self-renewal and specifically, how PI3K maintains GSK3-beta activity and inhibits an EMT.
The third Aim, will establish the exact conditions for early cell fate commitment to mesendoderm and how Wnt and TGF-beta synergize to pattern this cell type. Finally, we will investigate the use of GSK3-beta inhibitors as compounds that can promote uniform differentiation of hESCs. Understanding the mechanisms of hESC self-renewal is critical if we are to harness their full potential as a developmental model and as a therapeutic source of cells that can be used in regenerative medicine. Our understanding of hESC differentiation into different lineages is only poorly understood. This proposal will focus on a very early stage of cell fate commitment that is critical for differentiation into two key lineages. First, mesoderm which can give rise to blood, muscle and bone. Second, definitive endoderm which gives rise to pancreas, liver, lung, intestine and thyroid.
|Boward, Ben; Wu, Tianming; Dalton, Stephen (2016) Concise Review: Control of Cell Fate Through Cell Cycle and Pluripotency Networks. Stem Cells 34:1427-36|
|Foti, Rossana; Gnan, Stefano; Cornacchia, Daniela et al. (2016) Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program. Mol Cell 61:260-73|
|Li, Ben; Sun, Zhaonan; He, Qing et al. (2016) Bayesian inference with historical data-based informative priors improves detection of differentially expressed genes. Bioinformatics 32:682-9|
|Rivera-Mulia, Juan Carlos; Gilbert, David M (2016) Replication timing and transcriptional control: beyond cause and effect-part III. Curr Opin Cell Biol 40:168-78|
|Avery, John; Dalton, Stephen (2016) Methods for Derivation of Multipotent Neural Crest Cells Derived from Human Pluripotent Stem Cells. Methods Mol Biol 1341:197-208|
|Rivera-Mulia, Juan Carlos; Gilbert, David M (2016) Replicating Large Genomes: Divide and Conquer. Mol Cell 62:756-65|
|Wilson, Korey A; Elefanty, Andrew G; Stanley, Edouard G et al. (2016) Spatio-temporal re-organization of replication foci accompanies replication domain consolidation during human pluripotent stem cell lineage specification. Cell Cycle 15:2464-75|
|Singh, Amar M; Trost, Robert; Boward, Benjamin et al. (2016) Utilizing FUCCI reporters to understand pluripotent stem cell biology. Methods 101:4-10|
|Berger, Ryan P; Sun, Yu Hua; Kulik, Michael et al. (2016) ST8SIA4-Dependent Polysialylation is Part of a Developmental Program Required for Germ Layer Formation from Human Pluripotent Stem Cells. Stem Cells 34:1742-52|
|Soufi, Abdenour; Dalton, Stephen (2016) Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming. Development 143:4301-4311|
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