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| =The pancreas gene regulatory network=
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| Over the last couple of years, the zebrafish has become a major model organism to study vertebrate organogenesis. Initial studies showed that, albeit some minor differences, the essential components (transcription factors and signaling molecules) involved in pancreas organogenesis in zebrafish and mammals are conserved. Nonetheless, the gene network underlying pancreas development in zebrafish and mammals is incomplete because mainly based on epistatic relationships inferred from knockout phenotypes. In addition, recent surveys of the embryonic expression of microRNAs during zebrafish development revealed at least two that appear to be pancreas-specific. The function of these miRNAs in pancreas formation is unknown. What are the genes directly regulated by some of the major transcription factors involved in pancreas organogenesis (i.e. Ptf1, Pdx, Hb9, Isl1, Pax6, Nk2.2,...)? What are the target cis-regulatory modules bound by those factors? Are target genes regulated by these factors combinatorially? What is the role of microRNAs expressed in the pancreatic anlage during zebrafish embryogenesis? We will address those questions using a combination of ChIP-seq and SELEX assays, classical deletion studies, comparative genomics and other bioinformatics methods, as well as reverse genetics. The information obtained from these analyses will greatly improve our understanding of the complex network regulating pancreas formation and endocrine cell differentiation.
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| =ncRNAs and gene regulatory networks=
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| Specification of the mesoderm in Drosophila starts with the formation, in the precellular embryo, of nuclear gradient of a protein called Dorsal (Dl). Peak levels of this protein in the ventral part of the embryo activate the expression of twist (twi), which encodes a bHLH transcription factor. Twist in turns activates the expression of target genes that are required at various steps of mesoderm development -e.g. T48 (invagination of mesoderm precursors during gastrulation), dMef2 (segmentation and specification of muscle types), and tinman (formation of the heart). Twist also controls the expression of miR-1, a mesoderm-specific microRNA whose sequence and function have been conserved in mammals. We used whole-genome tiling arrays to identify additional ncRNAs expressed in the mesoderm. In contrast to miR-1, which is broadly expressed in the mesoderm, two other ncRNAs identified in our screen are expressed in progressively more restricted cell types at later stages of development, suggesting distinct and/or combinatorial functions in the specification, differentiation and morphogenesis of mesoderm derivatives. Our current focus is to characterize the function of these new non-protein coding genes using a combination of genetics, embryology, genomics, molecular, cell biological and computational approaches.
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