APOPTOTIC CHROMATIN · Investigating the link between histone phosphorylation and yeast 14-3-3 proteins in programmed cell death
6РП — Действия „Мария Кюри“
- Период
- 2006-07-01 → 2008-06-30
- Финансиране от ЕС
- 170 500 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите.
Накратко на български
Химичните промени по протеините-хистони в дрождите, като метилирането на аргинина H3R2, регулират структурата на хроматина. Тези процеси помагат да се разбере как се контролира активирането на гените и програмираната клетъчна смърт.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - APOPTOTIC CHROMATIN (Investigating the link between histone phosphorylation and yeast 14-3-3 proteins in programmed cell death)
Modifications on histones control important biological processes, such as transcription and apoptosis, through their effects on chromatin structure. Methylation at H3K4 by Set1 is found at the 5' end of active genes and contributes to transcription activation by recruiting chromatin remodelling enzymes. An adjacent arginine residue (H3R2) is also known to be methylated, but its genomic localisation and function in transcription was unknown. We showed that in mammalian cells as well as in yeast, chromatin is asymmetrically dimethylated at H3R2 (H3R2me2a). Using an antibody specific for H3R2me2a in ChIP-on-Chip analysis we determine the profile of this modification on the entire yeast genome. We find that H3R2me2a is enriched at all yeast heterochromatic loci, at inactive euchromatic genes and at the 3'-end of active genes. In all cases the pattern of H3R2 methylation is mutually exclusive with the presence of trimethylation at H3K4 (H3K4me3). This inverse correlation reflects the fact that methylation at H3R2 disrupts the ability of the Set1-complex to bind methylated H3K4 via its Spp1 component, resulting in inhibition of Set1-mediated trimethylation. These results indicate that H3R2me2a controls the global distribution of H3K4me3. In addition, we demonstrated that H3R2 is also monomethylated (H3R2me1) in yeast but that its functional characteristics are distinct from H3R2me2a: (a) monomethylated H3R2 does not inhibit methylation of H3K4; (b) it is present throughout the coding region of genes; and (c) it correlates with active transcription. Collectively, these results indicate that different H3R2 methylated states have defined roles in gene expression and provide the first mechanistic insight into the function of arginine methylation on chromatin.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Post-translational modifications of histones including acetylation and methylation, serve as signals for various cellular processes, such as, transcription, DNA repair, and cell signalling. Histone phosphorylation has recently been connected to programmed cell death, also known as apoptosis, in both mammals and yeast.Specifically, phosphorylation of serine 10 within histone H2B in the yeast S. cerevisiae has been linked to chromatin compaction during the late stages of apoptosis. Phosphorylation of this am ino acid residue is catalyzed by the yeast kinase Ste20. However, it still remains unknown how the activity of Ste20 towards H2B is controlled.Interestingly, Ste20 has been shown to interact with the yeast 14-3-3 proteins, bmh1 and bmh2, which play a role in the regulation of histone phosphorylation. Based on these findings and the fact that mammalian 14-3-3 proteins are implicated in the apoptotic process, we hypothesize that the bmh proteins are involved in cell death by associating with phosphorylated histones.The experiments outlined in this proposal are aimed to determine; 1) whether the bmh proteins have an apoptotic function in yeast, 2) whether the bmh proteins regulate the activity of Ste20, 3) whether the bmh proteins bind specifically to phosphorylated H2B-Ser10, and 4) whether induction of apoptosis affects the localization of bmh proteins.These experiments should provide a better knowledge of the molecular mechanisms that underlie the apoptotic process. It is critical to understand these mechanisms because a defect in the apoptotic pathway can often lead to human proliferative diseases such as cancer.Additionally, these studies will provide me with the opportunity to explore and learn to use yeast as an experimental model system. Most importantly, I will be exposed to new molecular approaches that will complement my existing scientific knowledge and thus, allow me to address crucial biological questions concerning chromatin structure in cells.
Оригинален текст от CORDIS (на английски).
Участници
- University of Cambridge · CambridgeКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз