Interactions between nucleosome-binding modules and catalytic domains of histone modifying enzymes
I am studying the transcriptional co-activator and histone acetyltransferase (HAT) p300, which is critical for regulating gene expression in mammalian cells. Many histone modifying and remodelling enzymes have one or more histone recognition modules, often near their catalytic domain. In our group, we have found evidence for an intramolecular interaction between the p300 bromodomain/PHD finger region and its HAT domain. Bromodomains can interact specifically with acetylated lysines residues.
In this project, I want to explore the functional consequence of the physical interaction between bromo/PHD finger region and HAT domain in p300 and investigate the generality of this intramolecular communication with other histone-modifying enzymes. In particular, I want to study the molecular basis for this regulation and validate our p300 working model, which distinguishes ON and OFF state of p300 HAT. Autoacetylation of the HAT activation loop plays a central role for the catalytic activity, as well as the presumed deacetylation by SIRT2. I want to shed more light onto p300 regulation, especially how the bromo/PHD – HAT interaction is involved in this process.
Specifically, I am intrigued by the fact that so many chromatin modifying and modulating enzymes are remarkably long (p300 has 2414 residues). One reason could be that the protein acts over some distance in chromatin. In the case of p300, this could relate to the recruitment of p300 to enhancers, while its catalytic domain is active on the regulated promoter. In my project, I wish to explore this hypothesis.
- 2014. The PHD finger of p300 influences its ability to acetylate histone and non-histone targets. Journal of Molecular Biology. 426: 3960-3972. doi: 10.1016/j.jmb.2014.08.011
- 2014. Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform. Journal of Molecular Biology. 426: 1677-1691. doi: 10.1016/j.jmb.2013.10.027
- Huser, D.; Gogol-Doring, A.; Lutter, T.; Weger, S.; Winter, K.; Hammer, E. M.; Cathomen, T.; Reinert, K.; Heilbronn, R. Integration preferences of wildtype AAV-2 for consensus rep-binding sites at numerous loci in the human genome. PLoS Pathog. 2010, 6, e1000985
Certified Engineer (Diplom-Ingenieur) in Medical Biotechnology
Technische Universität Berlin, Germany
Graduated with honors (Grade: 1.0)
Diploma Thesis at the Department of Virology, Charité Berlin
‘Characterization of Adeno-associated virus type 2 (AAV-2) integration pattern in HeLa cell clones’
Student research project at the Department of Virology, Charité Berlin
‘Identification and characterization of non-AAVS1-specific integration sites of Adeno-associated virus type 2 (AAV-2) using HeLa cell clones’
EU FP7 Marie Curie Initial Training Network:
Nucleosome Structure & Function across Biological Scales and Biological Function (Nucleosome4D)
Project title: Interactions between nucleosome-binding modules and catalytic domains of histone modifying enzymes: functional consequences