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Histone H4 hyperacetylation precludes histone H4 lysine 20 trimethylation
Department of Medical Chemistry and Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
Department of Medical Chemistry and Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
Department of Medical Chemistry and Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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2004 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 279, no 51, 53458-53464 p.Article in journal (Refereed) Published
Abstract [en]

Posttranslational modification of histones is a common means of regulating chromatin structure and thus diverse nuclear processes. Using a hydrophilic interaction liquid chromatographic separation method in combination with mass spectrometric analysis, the present study investigated the alterations in histone H4 methylation/acetylation status and the interplay between H4 methylation and acetylation during in vitro differentiation of mouse erythroleukemia cells and how these modifications affect the chromatin structure. Independently of the type of inducer used (dimethyl sulfoxide, hexamethylenebisacetamide, butyrate, and trichostatin A), we observed a strong increase in non- and monoacetylated H4 lysine 20 (H4-Lys20) trimethylation. An increase in H4-Lys20 trimethylation, however, to a clearly lesser extent, was also found when cells accumulated in the stationary phase. Since we show that trimethylated H4-Lys20 is localized to heterochromatin, the increase in H4-Lys20 trimethylation observed indicates an accumulation of chromatin-dense and transcriptionally silent regions during differentiation and during the accumulation of control cells in the stationary phase, respectively. When using the deacetylase inhibitors butyrate or trichostatin A, we found that H4 hyperacetylation prevents H4-Lys20 trimethylation, but not mono- or dimethylation, and that the nonacetylated unmethylated H4-Lys20 is therefore the most suitable substrate for H4-Lys20 trimethylase. Summarizing, histone H4-Lys20 hypotrimethylation correlates with H4 hyperacetylation and H4-Lys20 hypertrimethylation correlates with H4 hypoacetylation. The results provide a model for how transcriptionally active euchromatin might be converted to the compacted, transcriptionally silent heterochromatin.

Place, publisher, year, edition, pages
2004. Vol. 279, no 51, 53458-53464 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14127DOI: 10.1074/jbc.M409099200OAI: oai:DiVA.org:liu-14127DiVA: diva2:22681
Available from: 2006-11-06 Created: 2006-11-06 Last updated: 2009-06-03
In thesis
1. Chromatin, histones, and epigenetic tags
Open this publication in new window or tab >>Chromatin, histones, and epigenetic tags
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The fundamental building blocks of chromatin are the nucleosomes. Each such unit is composed of about 200 bp of DNA, the well-conserved core histones (H2A, H2B, H3 and H4) and a linker histone (H1). The DNA is wound around two dimers of H2A–H2B and a tetramer comprising two molecules each of H3 and H4, and there is approximately one linker histone molecule positioned on the exterior of the DNA–protein octamer complex. The nucleosome directs the various structural transitions in chromatin that are needed for proper transcriptional regulation during differentiation and development of the organism in question. The gene activity can be regulated by different histone variants, DNA–protein interactions, and protein–protein interactions, all of which are influenced by the enormous amounts of post-translational modifications that occur in the histone tails. The research underlying this thesis focused on different aspects of post-translational modifications during aging, differentiation, and progression of the cell cycle, and also on expression of linker histone variants and linker histone-chromatin interactions in a variety of cells and tissues.

The present results are the first to show that H4 can be trimethylated at lysine 20 in mammalian cells. The trimethylated H4K20 was found in rat kidney and liver at levels that rose with increasing age of the nimals, and it was also detected in trace amounts in human cell lines. Furthermore, in differentiating MEL cells, trimethylated H4K20 was localized to heterochromatin, and levels of trimethylated H4K20 increased during the course of cell differentiation and were correlated with the increasing compaction of the chromatin.

The chromatin of terminally differentiated chicken and frog erythrocytes is highly condensed, and the linker histone variants it contains vary between the two species. Cytofluorometric analyses revealed that the linker histones in the chicken erythrocytes exhibited higher affinity for chromatin than did those in the frog erythrocytes. Characterization of the H1° in frog erythrocytes proved it to be the H1°-2 subvariant. Other experiments demonstrated that normal human B lymphocytes expressed the linker histone variants H1.2, H1.3, H1.4, and H1.5, and that B cells from patients with B-CLL expressed the same variants although in different amounts. The most striking dissimilarity was that amounts of H1.3 in the cells were decreased or undetectable in some samples. Sequencing did not discern any defects in the H1.3 gene, and thus the absence of H1.3 is probably regulated at the post-translational level. It was also observed that the levels of linker histone phosphorylation in EBV-transformed B lymphocytes were already increased in the G1 phase of the cell cycle, which is earlier than previously thought. This increase in phosphorylation is probably responsible for the lower affinity of linker histones for chromatin in EBV-transformed cells in the G1 phase of the cell cycle.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2006
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 960
Keyword
Chromatin, histones, histone variants, epigenetics, histone H4 methylation, linker histone phosphorylation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-7687 (URN)91-85523-10-0 (ISBN)
Public defence
2006-10-27, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 00:00 (English)
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Available from: 2006-11-06 Created: 2006-11-06 Last updated: 2009-03-04

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