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

Descriptions

Other title
Subject/Keyword
chromatin remodeling
telomere
heterochromatin
yeast
nuclear pore complex
epigenetic gene regulation
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Van de Vosse, David W
Supervisor and department
Wozniak, Richard W (Cell Biology)
Examining committee member and department
Wozniak, Richard W (Cell Biology)
Aitchison, John D (Cell Biology)
Brickner, Jason H (Molecular Biosciences, Northwestern University)
Schultz, Michael C (Biochemistry)
Rachubinski, Richard A (Cell Biology)
Department
Department of Cell Biology
Specialization

Date accepted
2012-06-21T15:53:20Z
Graduation date
2012-04
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3WB0C
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Van de Vosse, D.W., Wan, Y., Aitchison, J.D., and R.W. Wozniak. (2011). Role of the nuclear envelope in genome organization and gene expression. Wiley Interdisciplinary Reviews Systems Biology and Medicine. 3(2), 147-166.Alber, F., Dokudovskaya, S., Veenhoff, L.M., Zhang, W., Kipper, J., Devos, D., Suprapto, A., Karni-Schmidt, O., Williams, R., Chait, B.T., Sali, A., and M.P. Rout. The molecular architecture of the nuclear pore complex. Nature. 2007;450(7170):695-701.Sun, J.Q., Hatanaka, A., and M. Oki. Boundaries of transcriptionally silent chromatin in Saccharomyces cerevisiae. Genes Genet Syst. 2011;86(2):73-81.Taddei, A., Schober, H., and S.M. Gasser. The budding yeast nucleus. Cold Spring Harb Perspect Biol. 2010;2:a000612.

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