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Title: Phosphorylation and distribution of High-Mobility Group protein HMGN1 in the context of Immediate-Early (IE) gene induction
Author: Pogna, Edgar Allan
ISNI:       0000 0004 2745 6569
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Eukaryotic genomes are highly organized and packaged into chromatin, a complex structure formed of proteins and DNA, in which the basic repeating unit is the nucleosome. Chromatin can be arranged in condensed or relaxed structures influencing accessibility of proteins that regulate transcription, replication, recombination and repair. One class of transiently chromatin-associated proteins is the High-Mobility Group (HMG) protein family. HMG proteins are subdivided into three subgroups: HMGA, HMGB and HMGN. HMGN1, the subject of this study, is a prominent member of the HMGN (High-Mobility Group Nucleosome-binding) protein family, the only HMG proteins that specifically binds to the nucleosomes. HMGNs are maintained in dynamic balance between nucleosome-associated and nucleosome-free pools. Regulation of chromatin involves several enzymatic activities that modify specific residues on chromatin proteins, which may influence these interactions. While associated with nucleosomes, HMGNs can interfere with some modifications of histone tails. Modification of HMGN1 on specific residues and post-translational modification (PTM) of histones are concomitantly regulated by the complex signalling networks associated with the induction of immediate early (IE) genes. Induction of IE genes is associated with phosphorylation of HMGN1 which has been suggested to increase the rate of dissociation of HMGN1 from the nucleosome, thus allowing access and modification of histone tails. My research has been focused on characterizing HMGN1 isoforms present in different cellular compartments and at different time-points during IE gene induction with various stimuli, including epidermal growth factor (EGF), anisomycin (An) and 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, I investigated the localization of HMGN1 within the nucleus and at specific IE gene loci, especially at sites where post-translationally modified histones are localised. In my analysis only the phosphorylation at serine 6 of HMGN1 shows a correlation with gene induction. Analysis of DNA sequences from chromatin immunoprecipitation (ChIP) has shown that HMGN1 is present at equal levels in active and inactive genes. It appears that HMGN1 localization on DNA is not dictated by a particular preference for any gene elements such as promoters, exons, introns or gene termination sequences.
Supervisor: Mahadevan, Louis Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry ; chromatin ; signalling