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If you have a question about this talk, please contact Kate Davenport.
One major research interest in our laboratory is focused on understanding the regulation of stem cell fate decision processes. A second interest is the use of stem cell approaches to develop patient-specific models of inherited diseases. Both of these efforts currently involve the use of embryonic or induced pluripotent stem cells (ESC and iPSC, respectively). We have taken a broad, quantitative systems biology approach to unravel the regulatory mechanisms that are necessary for maintaining and reacquiring the self-renewing pluripotent state. Specifically, we utilize short hairpin (sh) RNA techniques to perform loss-of-function perturbations in mouse (m) and human (h) ESC . We have developed a genetic complementation strategy to effectively “replace” any gene-product with a version that can be controlled by a small molecule added to cell cultures. Using this approach, we have perturbed the expression of numerous key regulatory molecules such as transcription factors, epigenetic regulators as well as components of signaling pathways. After perturbation, we monitors global molecular changes aver time. These changes include: chromatin modifications, mRNA levels, microRNA levels and the nuclear proteome. These studies provide a “real time” view of biological information processing that occurs during and is responsible for a transition in ESC fate. An essential component of our studies is computational biology. This has allowed us to analyze and integrate the large amount of information that is acquired. Computational analyses have also facilitated the generation of models of how regulatory networks function during changing cell fates. We have gained numerous novel insights into ESC regulation. Several of these include: how the Esrrb transcription factor controls pluripotency, genotoxic stress response mechanisms that regulate ESC and translational control as an under-appreciated aspect of cell fate regulation. In our second major research focus, we have utilized iPSC reprogramming to develop models of human genetic diseases. In particular, we have developed patient-specific models of cardiac disorders and are expanding our efforts to include metabolic diseases. Very recently, we have used direct programming technologies to directly convert mouse fibroblast cells into hemogenic endothelium. This tissue is the origin of hematopoietic stem and progenitor cells during fetal development. The programming is fairly efficient and requires four transcription factors. An additional exciting feature of these results is our ability to “kick start” the hemogenic endothelial developmental program, providing an in vitro avenue for in-depth analyses. We are currently extending the direct programming efforts to the human system.
This talk is part of the Cancer Research UK Cambridge Institute Seminars in Cancer series.
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