A role for the nuclear pore complex protein Nup170p in defining chromatin structure and regulating gene expression

  • Author / Creator
    Van de Vosse, David W
  • The spatial organization of chromosomal loci within the nucleus can have a significant influence on transcriptional activity. Transcriptionally active genes are generally positioned within the nuclear interior. By contrast, the positioning of genes at the nuclear periphery is often correlated with transcriptional silencing as evident by the preferential localization of condensed, transcriptionally silent heterochromatin at the nuclear envelope (NE). This generality of the NE fostering silencing is lost at regions of the NE occupied by nuclear pore complexes (NPCs). Here heterochromatin bound to the inner nuclear membrane is abruptly interrupted at the nucleoplasmic face of NPCs by associated, transcriptionally active euchromatin channels. Thus, NPCs are positioned at the interface between heterochromatin and euchromatin. These morphological observations have long led to the idea that NPCs play an important role in defining chromatin structure and in gene expression. In recent years, this premise has been reinforced by studies in the yeast model system. For example, both active and silenced genes have been detected in association with NPCs. These and other observations have led ourselves and others to hypothesize that NPCs function in the transition of chromatin between transcriptional states. We have investigated this role of NPCs in chromatin organization through analyses of its components. We have focused on Nup170p, as the role of this protein in transcriptional repression was indicated by phenotypic manifestations suggestive of derepression of cell-type-dependent genes. We showed that Nup170p genetically interacts with multiple chromatin complexes involved in transcriptional silencing. Consistent with these observations, we detected Nup170p in physical association with the RSC chromatin-remodeling complex, and both the RSC complex and Nup170p are required for repression of subtelomeric genes and the regulation of ribosomal protein (RP) gene expression. Moreover, Nup170p associates with and is required for proper chromatin structure at these loci. The subtelomeric chromatin association of Nup170p is mediated by its interaction with the silencing factor Sir4p. Conversely, the binding of Sir4p to telomeres and their normal association with the inner nuclear membrane are dependent on Nup170p. Importantly, these interactions are prominent during periods of telomere association with the NE at the end of mitosis.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
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  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Cell Biology
  • Supervisor / co-supervisor and their department(s)
    • Wozniak, Richard W (Cell Biology)
  • Examining committee members and their departments
    • Schultz, Michael C (Biochemistry)
    • Brickner, Jason H (Molecular Biosciences, Northwestern University)
    • Rachubinski, Richard A (Cell Biology)
    • Aitchison, John D (Cell Biology)
    • Wozniak, Richard W (Cell Biology)