NUCLEAR STRUCTURE AND GENE EXPRESSION

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Our program is focused on interrelationships of nuclear structure and gene expression. That are functionally linked to modified transcriptional control in transformed and tumor cells. Our working hypothesis is that parameters of nuclear structure support cell growth and phenotypic properties of normal and tumor cells by facilitating the organization of chromosomes, genes, transcripts and regulators within the dynamic 3- dimensional context of nuclear architecture. Investigators at the University of Massachusetts Medical School have been instrumental in establishing the conceptual and experimental basis for multiple parameters of nuclear organization in gene regulation. Key contributions to the emerging recognition that structural components of the nucleus mediate transcription and the processing of gene transcripts have been provided by collaborations among our program project investigators. This team approach has advanced understanding of intranuclear trafficking of transcription factors to sites that support gene expression, the regulation of chromatin remodeling and chromosome segregation, the structural and functional properties of the nuclear matrix and characteristics of functional novel domains. We are committed to experimentally defining novel mechanisms that relate changes in nuclear morphology to aberrant growth in tumor cells from the perspective of perturbations in the subnuclear representation and targeting of nucleic acid and gene regulator proteins. Mechanisms by which nuclear structure integrates physiological regulatory signals that support gene expression are being addressed. We are investigating post- translational modifications of histones that support chromatin remodeling to render promoter elements accessible to transcription factors and facilitate synergism of activities at independent gene regulatory sequences. Regulation of centrosome organization is being pursued in relation to altered assembly of the mitotic apparatus, chromosome segregation and translocation, as well as aneuploidy in tumor cells. Our objective is to optimize the combination of cellular, biochemical and molecular approaches, together with in vitro and in vivo model systems, to define mechanisms by which nuclear architecture supports fidelity of gene expression. Equally important, we will gain insight into parameters of nuclear organization that are associated.