Epigenetic Mechanisms Underlying Stem Cell Decision Making
In this project area, IGERT Trainees will apply bioinformatics approaches and advances in genomics to define the epigenetic mechanisms modulating commitment of stem cells into specific lineages (see Fig. 10). Epigenetic memory is an inheritable mechanism of gene expression that allows each cell to have a specific identity. This project will focus on the formation of oligodendrocytes, the cells of the central nervous system that form the nerve insulating substance, myelin. The proposed study is relevant to several diseases, ranging from neonatal dysmyelination to nutritional deficiencies (i.e. low iron diet) or hormonal deficiencies to developmental disorders of the preterm infant to multiple sclerosis.
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Fig. 10. Work-flow among the investigators involved in the IGERT project. A: Casaccia-Bonnefil's lab will provide the expertise in neurobiology and microarray data on precursor cells prior to differentiation. B: Androulakis' lab will provide a systems network analysis of the data and identify potential transcription factor relations. C: Cai's laboratory will define the conserved elements in the untranslated regions of the genes identified. D: A whole-genome analysis of oligodendrocyte differentiation will be performed. E: hybridization data will be analyzed in the Pirrotta laboratory. |
The Casaccia-Bonnefil laboratory (BMB) has identified histone deacetylation as a critical event for oligodendrocyte differentiation. Trainees would first generate a series of microarray data of neural precursors differentiated into oligodendrocytes in the presence and absence of histone deacetylase inhibitors (see Fig. 10). These data, together with the analysis of published microarray studies by Y. Androulakis (BME) and of the conserved elements among clusters of co-expressed genes by L. Cai (BME) will serve as a platform to develop dynamic regulatory models. These predictions will need to be further validated in cultured cells using chromatin immunoprecipitation. Once the validated transcription factors have been established, IGERT Trainees will interrogate the genome in the Pirrotta lab (Biochemistry) via a state-of-the art technology called Chip-on-Chip that allows the analysis of genome-wide modifications of chromatin components. In summary, IGERT will identify putative regulatory networks to address the question of how oligodendrocytes are generated.
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