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Chromatin modifiers and their function

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Název: Chromatin modifiers and their function
Autoři: Halls, K. S.
Informace o vydavateli: University of Cambridge, 2008.
Rok vydání: 2008
Sbírka: University of Cambridge
Témata: 571.6
Popis: The aim of my work was to investigate enzymes that potentially modify chromatin and identify possible functions. SET domain containing proteins can catalyse histone lysine methylation. Riz and Blimp are members of the PRDM subfamily of the SET-domain protein group. PRDM proteins contain amino acid substitutions at conserved sites within the SET domain and it is thought that these mutations may inactivate histone methyltransferase (HMT) activity. I have investigated potential functions for this subfamily. My results suggest that the Riz and Blimp bind and demethylate histones in vitro. Set8 is another SET-domain containing protein, but it is catalytically active. Set8 is a member of the SET1 subfamily and it methylates histone H4 at amino acid lysine 20 (H4K20). I generated stable cell lines that express increased levels of Set8 to investigate the physiological role of this enzyme. Overexpression of the enzyme decreases the rate of cellular proliferation and partially reserves a transformed phenotype. Furthermore, increased levels of Set8 affect the cell cycle and my results suggest this could be due to misregulation of mitosis. AKT and S6K are kinases that phosphorylate serine and threonine residues that reside within similar amino acid consensus sequences. I demonstrate that these enzymes phosphorylate histones in vitro, and identify H2AT16 and H3T45 as two phosphorylation sites. I provide evidence for their existence in vivo and in addition, my data implicates AKT as the enzyme responsible for H2AT16ph in vivo. H2AT16ph is associated with mitosis, localising to mitotic chromosomes. In contrast H3T45ph is upregulated during apoptosis in HL-60 cells. Many histone-modifying enzymes have now been linked to a variety of diseases. Analyses of these enzymes should assist with the search for treatments. My results provide additional information into the function of these enzymes. Such data is important, as unlike genetic mutations, aberrant epigenetic modifications are potentially reversible. Therefore, enzymes that catalyse these marks provide potential targets for therapeutic purposes.
Druh dokumentu: Electronic Thesis or Dissertation
Jazyk: English
Přístupová URL adresa: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599879
Přístupové číslo: edsble.599879
Databáze: British Library EThOS
Popis
Abstrakt:The aim of my work was to investigate enzymes that potentially modify chromatin and identify possible functions. SET domain containing proteins can catalyse histone lysine methylation. Riz and Blimp are members of the PRDM subfamily of the SET-domain protein group. PRDM proteins contain amino acid substitutions at conserved sites within the SET domain and it is thought that these mutations may inactivate histone methyltransferase (HMT) activity. I have investigated potential functions for this subfamily. My results suggest that the Riz and Blimp bind and demethylate histones in vitro. Set8 is another SET-domain containing protein, but it is catalytically active. Set8 is a member of the SET1 subfamily and it methylates histone H4 at amino acid lysine 20 (H4K20). I generated stable cell lines that express increased levels of Set8 to investigate the physiological role of this enzyme. Overexpression of the enzyme decreases the rate of cellular proliferation and partially reserves a transformed phenotype. Furthermore, increased levels of Set8 affect the cell cycle and my results suggest this could be due to misregulation of mitosis. AKT and S6K are kinases that phosphorylate serine and threonine residues that reside within similar amino acid consensus sequences. I demonstrate that these enzymes phosphorylate histones in vitro, and identify H2AT16 and H3T45 as two phosphorylation sites. I provide evidence for their existence in vivo and in addition, my data implicates AKT as the enzyme responsible for H2AT16ph in vivo. H2AT16ph is associated with mitosis, localising to mitotic chromosomes. In contrast H3T45ph is upregulated during apoptosis in HL-60 cells. Many histone-modifying enzymes have now been linked to a variety of diseases. Analyses of these enzymes should assist with the search for treatments. My results provide additional information into the function of these enzymes. Such data is important, as unlike genetic mutations, aberrant epigenetic modifications are potentially reversible. Therefore, enzymes that catalyse these marks provide potential targets for therapeutic purposes.