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dc.contributor.advisorSchirmer, Ericen
dc.contributor.advisorSawyer, Lindsayen
dc.contributor.authorBatrakou, Dzmitry G.en
dc.date.accessioned2015-02-26T15:39:56Z
dc.date.available2015-02-26T15:39:56Z
dc.date.issued2012-11-30
dc.identifier.urihttp://hdl.handle.net/1842/9981
dc.description.abstractHistorically, our perception of the nuclear envelope has evolved from a simple barrier isolating the genome from the rest of a cell to a complex system that regulates functions including transcription, splicing, DNA replication and repair and development. Several recent proteomic studies uncovered a great variety of nuclear envelope transmembrane proteins (NETs). Diseases associated with several nuclear envelope proteins, mostly NETs, affect many tissues e.g. muscle, adipose tissue, skin, bones. Many NETs of the inner nuclear membrane have been shown to interact with chromatin, suggesting that their influencing gene expression might explain NET roles in disease. This work is focused on finding novel interactions of NETs with chromatin. First, SUN2 post-translational modifications were analysed and the effect of phosphomimetic and phospho-null mutants on heterochromatin and the cytoskeleton was tested by overexpression. However, no obvious changes were found. Second, several tissue-preferential NETs were tested in an adipocyte differentiation system. NET29 changed chromosome 6 position in pre-adipocytes. This matched changes in chromosome positioning that occur during adipocyte differentiation when NET29 is normally induced. Post-translational modifications of NET29 are likely to play a vital role in this process because a phospho-null mutant dominantly blocked chromosome repositioning. The effect of over-expression and down-regulation of NET29 on transcription was tested and results suggest that NET29 negatively regulates expression of myogenic genes during adipogenesis. This thesis is split into six chapters. Chapter I is an overview of the nuclear envelope, adipogenesis and chromatin remodelling, Chapter II is a detailed description of methods used in this study. Chapter III focuses on post-translational modifications of SUN2, as well as trials to identify novel partners of SUN2. Chapter IV and V deal with a novel nuclear envelope transmembrane protein and its role in adipogenesis. Finally, the last chapter includes a discussion and recommended future directions.en
dc.contributor.sponsorDarwin Trust of Edinburghen
dc.contributor.sponsorWellcome Trusten
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionBatrakou DG, Kerr ARW and Schirmer EC. Comparative proteomic analyses of the nuclear envelope and pore complex suggests a wide range of heretofore unexpected functions. J Proteomics 2009en
dc.relation.hasversionKorfali N, Srsen V, Waterfall M, Batrakou DG, Pekovic V, Hutchison CJ and Schirmer EC. A Flow Cytometry-Based Screen of Nuclear Envelope Transmembrane Proteins Identifies NET4/Tmem53 as Involved in Stress-Dependent Cell Cycle Withdrawal. PLoS ONE 2011en
dc.relation.hasversionKorfali N, Wilkie GS, Swanson SK, Srsen V, Batrakou DG, Fairley EAL, Malik P, Zuleger N, Goncharevich A, de Las Heras J, Kelly DA, Kerr ARW, Florens L and Schirmer EC. The leukocyte nuclear envelope proteome varies with cell activation and contains novel transmembrane proteins that affect genome architecture. Mol. Cell Proteomics 2010en
dc.relation.hasversionMalik P, Korfali N, Srsen V, Lazou V, Batrakou DG, Zuleger N, Kavanagh DM, Wilkie GS, Goldberg MW and Schirmer EC. Cell-specific and lamin-dependent targeting of novel transmembrane proteins in the nuclear envelope. Cell. Mol. Life Sci. 2010en
dc.relation.hasversionWilkie GS, Korfali N, Swanson SK, Malik P, Srsen V, Batrakou DG, de Las Heras J, Zuleger N, Kerr ARW, Florens L and Schirmer EC. Several novel nuclear envelope transmembrane proteins identified in skeletal muscle have cytoskeletal associations. Mol. Cell Proteomics 2010en
dc.subjectnuclear envelopeen
dc.subjectadipogenesisen
dc.titleNuclear envelope transmembrane proteins in differentiation systemsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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