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Dumitru Andrei IacobasAssistant Professor Kennedy Center
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Our laboratory uses a variety of molecular and computational biology techniques to identify and characterize the transcellular, connexin-dependent transcriptomic networks that control essential processes such as myelination, heart rhythm, and inflammatory response. Experimental data are then used to develop mathematical models and computer simulation programs of intercellular signaling in complex structures. The connexins (Cx) comprise a family of topologically similar transmembrane proteins that can assemble to form gap junction channels between cells within vertebrate animals. Such intercellular channels provide cytoplasmic continuity between the interconnected cells and play crucial roles in cell growth, differentiation and synchronous activity within specialized tissues. Through extensive microarray studies we found that, regardless subtype and tissue or cell line, connexins are transcriptomic hubs whose expression modulates not only the expression level, but also the strength of the transcription control and expression interlinkages of numerous other genes. Moreover, the regulomes of connexin deficient tissues are largely predictable from the corresponding connexin expressomes of the wildtypes. Together with the highly significant overlap between transcriptomic alterations in connexin knockout and knockdown cells, these results suggest that the widespread changes more likely reflect Connexin-Dependent Gene Regulatory Networks rather than developmental compensation for the missing gene. In such networks, linkage partners are rearranged and strengths modified in both transgenic and diseased animals, in response to pathologic or stressful conditions, as well as during development. The observed profound remodeling of the web of transcription factors and components of the polymerase III gene cluster in connexin deficient tissues may provide a molecular explanation for the downstream and parallel “ripples” of phenotypic change resulting from single gene manipulations. Selected Publications
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