Mitochondrial reprogramming in cell fate conversion and neural specification
In this project, we seek to dissect the potentially instructive role of bioenergetic restructuring for cell fate conversion and neural specification in particular. We will first focus on defined cellular states (fibroblasts, iPSCs, neural progenitors, neurons, and astrocytes) to map their mitochondrial/metabolic signature and the downstream effects on the epigenetic landscape. We will then analyze the mechanistic function of mitochondria and energy metabolism during reprogramming to iPSCs and upon glial and neuronal differentiation, by altering nutrient availability and by chemical and genetic manipulation of critical mitochondrial and metabolic regulators. Finally, we wish to integrate the obtained data to computationally build a metabolic map of cell identities. This will be coupled to mitochondrial-related high throughput assays to possibly identify enablers of metabolic-driven cellular conversions. Overall, these studies may lead to a better understanding of the importance of mitochondria and metabolism for brain development and for the control of cell fate plasticity and specification.
|Figure 1: Metabolic restructuring during the induction of pluripotency and epigenetic crosstalk. Our previous works demonstrate that key metabolic players are differentially expressed in hESCs (red) compared to somatic fibroblasts (black) and that their reconfiguration takes place during reprogramming to iPSCs (orange). This metabolic restructuring might contribute to the rewiring of the epigenetic state (blue arrows) through histone and chromatin modifications.|
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- PMID: 20201066