Universiẗat, Diss., 2002--Heidelberg.

Splicing is the process when introns gets removed and exons are spliced together. This is an important step to form a clean mRNA with no unnecessary sequences that could interrupt protein synthesis. There are different types of splicing and some of them need a complex called spliceosome. The spliceosome requires ATP, small nuclear RNAs and splicing factors. The spliceosome and the process splicing can be regulated by epigenetics, and one epigenetic mechanism is histone modification. There are four types of histone modifications; methylation, phosphorylation, ubiquitination and acetylation. They regulate splicing to different extents by altering the chromatin structure, affect the assembly of the spliceosome and regulate the attraction of splicing factors. This review will investigate if histone modifications affect splicing and to what extent. Suggestions for further research regarding the relationship between splicing and histone modifications will also be provided. The review is based on 30 articles and two books and the search was conducted between 30th of March 2020 and 13th of April 2020. Ubiquitination and phosphorylation have a minor effect on splicing meanwhile methylation and acetylation affect splicing in great extent.

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"Histone deacetylases (HDACs) have become one of the leading areas of research for cancer, neurodegenerative diseases, diabetes, obesity, and inflammation. Although HDACs are currently expressible in mammalian cultures and yeast, it is important to explore other cost effective options. Here it is shown that class I HDACs are expressible in insect cells. As well as expressing full length domains for class I HDACs, predicted active domains have also been expressed. This information can be utilized in many areas for future research including identifying unique sites to allow development of specific inhibitors for each HDAC, and developing a better understanding of the specific role of each HDAC. "

La stabilité de l’information génétique est d’une importance cruciale pour la fonction normale et la reproduction de tous les êtres vivants. Or, la capacité de fertilisation chez l’homme est habituellement mesurée en considérant la concentration, la motilité et la morphologie des spermatozoïdes. Cependant, ces paramètres ne prennent pas en considération l’intégrité du matériel génétique. Pourtant, de fortes évidences démontrent que la spermiogenèse, qui est la phase haploïde de la spermatogenèse durant laquelle se produit un important remodelage de la chromatine, serait une importante source d’instabilité génétique. En effet, des bris transitoires de l’ADN surviennent durant la spermiogenèse au même moment que l’hyperacétylation des histones H4 et la stimulation de l’hyperacétylation de H4 par traitement à la trichostatine A stimule la formation de cassures dans l’ADN. Ainsi, des histones acétyltransférases (HATs) pourraient affecter la compaction et l’intégrité de l’ADN et par conséquent le potentiel fertilisant du gamète mâle. Il est donc important d’identifier l’histone acétyltransférase impliquée dans l’hyper acétylation des histones H4 durant la spermiogenèse, puisqu’il s’agit d’un processus possiblement important pour la fertilité de l’homme. À la suite d'analyses par spectrométrie de masse d’échantillons protéiques de testicules de souris possédant la propriété d'acétyler l’histone H4 aucune HAT n’a été identifée. Par contre, la protéine mitochondriale ACAT1, qui catalyse la transformation réversible de deux acétyl-CoA en CoA et acétoacétyl-CoA, a été détectée. Ces observations permettent d’émettre l’hypothèse que cette protéine pourrait jouer un rôle dans la spermiogenèse en augmentant le niveau d’acétyl-CoA chez les spermatides en élongation. En effet, puisque selon mes résultats les histones H4 sont en mesure de s’auto-hyperacétyler, on peut supposer qu’une augmentation du niveau d’acétyl-CoA causerait une acétylation de ces histones à l’échelle du génome, permettant ainsi la poursuite de la spermiogenèse et éventuellement la formation de spermatozoïdes matures et fonctionnels.

Post-translational modification (PTM) of proteins is known to be a method by which protein function can be regulated. The addition of selected chemical groups at specific amino acid residues can act as a switch by which the function of a modified protein can be attenuated. Histones are a group of proteins which are found in the nucleus of eukaryotic cells and interact with DNA, providing it with a structural foundation upon which the chromosome is built. Histone proteins have numerous sequence variants and are known to be extensively post-translationally modified in a dynamic manner. These modifications have a direct effect on the interacting DNA resulting in increasing or decreasing levels of gene transcription. Advancements in analytical instrumentation, when coupled to high resolution separation techniques permit the analysis of increasingly complex biological mixtures. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) offers unrivalled mass resolving power and mass measurement accuracy, allowing the detailed study of mixtures of intact proteins and their post-translational modifications. These features have been exploited to provide a global view of the PTMs of histone proteins. The work contained within this thesis is a study, by FT-ICR MS, of the modifications of one of the most extensively modified histone proteins; histone H4. Firstly, the modifications of histone H4 were examined after treatment with a potent histone deacetylase inhibitor across several cell lines. The cell lines chosen showed a varying response to treatment with the inhibitor. From the cell lines tested, two which responded differently were further interrogated to elucidate the order in which acetylation occurs in the N-terminal region. Secondly, the modifications of histone H4 were analyzed after exposure to lactic acid over multiple treatment times. Lactic acid is a metabolic by-product, and is of interest when considering the Warburg effect and its role in tumorigenesis. Exposure of cells to levels of lactic acid which can be present under anaerobic conditions (i.e. during intense exercise) showed that lactate is able to inhibit histone de-acetylation. The resulting increase in hyper-acetylated forms of histone H4 could be potentially linked to increased gene expression, a typical observation in tumorigenic cells. Finally, using a mouse model for the neurological condition Rett Syndrome, the posttranslational modifications of histone H4 were investigated. The primary cause of Rett Syndrome is mutation of the DNA binding protein methyl CpG binding protein 2 (MeCP2). MeCP2 has been associated with multiple intracellular functions, one of which is chromatin remodelling. The work carried out showed a link between MeCP2 mutation and tri-methylation of histone H4. In addition, the tri-methylation was not solely identified through the presence of tri-methylated fragments in fragmentation mass spectra. Interestingly, the neutral loss of a methylene group was observed extensively during fragmentation of tri-methylated species. This unreported phenomenon made interpretation of spectra difficult; however, ultimately served as a useful marker for this modification.

Histone H1, or linker histone, are unique histones that bind to the nucleosome to facilitate higher order chromatin structure. The linker histones, when compared to the core histones that make up the nucleosome, are poorly understood especially in plants. Linker histones are vital for plant development as well as for cell cycle regulation, sharing many qualities with animal linker histones. In this report, the first two parts introduce the current literature of H1, including result from non-plant systems, and the third section is a research proposal describing a research project to elucidate the roles of linker histones on the regulation of FLOWERING LOCUS C (FLC) in Arabidopsis thaliana. / text

Thèse (M.Sc.)--Université Laval, 2005. / Titre de l'écran-titre (visionné le 23 février 2006). Bibliogr.

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request

Epigenetic regulation is a mechanism by which heritable changes in gene expression are controlled by chromatin status rather than primary DNA sequence. Changes in chromatin structure affect accessibility of DNA elements to the transcriptional machinery and thus affect transcription activity of the gene. A key event in this process is reversible modification of core histones, which is catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDs, HDAs, or HDACs). In general, histone deacetylation is related to transcriptional gene silencing, whereas acetylation is associated with gene activation.To study the role of histone deacetylase in plant gene regulation and development, we generated constitutive antisense histone deacetylase 1 (CASH) transgenic plants. AtHD1 is a homolog of RPD3 protein, a global transcriptional regulator in yeast. Expression of the antisense AtHD1 caused dramatic reduction in endogenous AtHD1 transcription, resulting in accumulation of acetylated histones. Down-regulation of histone deacetylation caused a variety of growth and developmental abnormalities and ectopic expression of tissue-specific genes. However, changes in genomic DNA methylation were not detected in repetitive DNA sequences in the transgenic plants.We also identified a T-DNA insertion line in exon 2 of AtHD1 gene (athd1-t1), resulting in a null allele at the locus. The complete inhibition of the AtHD1 expression induced growth and developmental defects similar to those of CASH transgenic plants. The phenotypic abnormalities were heritable across the generations in the mutants. When the athd1-t1/athd1-t1 plants were crossed to wild-type plants, the mutant phenotype was corrected in the F1 hybrids, which correlated with the AtHD1 expression and reduction of histone H4 Lys12 acetylation. Microarray analysis was applied to determine genome-wide changes in transcriptional profiles in the athd1-t1 mutant. Approximately 6.7% (1,753) of the genes were differentially expressed in leaves between the wild-type (Ws) and the athd1-t1 mutant, whereas 4.8% (1,263) of the genes were up- or down-regulated in flower buds of the mutant. These affected genes were randomly distributed across five chromosomes of Arabidopsis and represented a wide range of biological functions. Chromatin immunoprecipitation assays indicated that the activation for a subset of genes was directly associated with changes in acetylation profiles.