Covalent modifications of histones can regulate all DNA dependent processes such as transcription, replication, DNA repair etc. We have identified and functionally characterized novel types and sites of histone modifications and their role in disease processes (Kebede et al., 2017; di Cerbo et al., 2014: Pradeepa et al., 2016). We showed for the first time that histone modifications can be causative for transcription (Tropberger et al., 2013). Our aim is to unravel how histone modifications in the core of the nucleosome regulate cellular functions, development and their deregulation in diseases such as cancer or diabetes.
Unlike modifications on histone tails, which are thought to execute their functions by recruiting chromatin ‘readers’, how modifications in the nucleosome core affect cellular function is not understood. This project we will focus on acetylation and succininylation on the lateral surface of the histone octamer (especially at lysines in contact to the DNA) and their impact on transcription, chromatin dynamics and nuclear organization. We will team up with the lab of Wendy Bickmore (MRC) where the student will study 4D chromatin organisation (Benabdallah et al., 2019) and develop synthetic biology tools in order to trace and manipulate individual modifications as well as synergistic effects of multiple acetylations. This will build on a previous collaboration between our labs where we identified lateral surface modifications as novel marks to predict active enhancers genome-wide (Pradeepa et al., 2016).
This project includes the possibility to be part of a dynamic and international team, learn state of the art technologies both in Munich and Edinburgh (such ChIP, single cell CUT@Tag, microC, capture HiC, Crispr/Cas9 mediated manipulations, imaging techniques including smFISH, as well as in vitro chromatin reconstitutions and in vitro transcription but also data analysis and integration). It requires the motivation to develop and execute the next breakthrough ideas in an interdisciplinary and scientifically stimulating environment. We will be using diverse model systems such as mouse ES cells (including their differentiation) and human cancer cells but also chromatin biochemistry to gain for the first time mechanistic insights in the mechanism of action of combinations of these modifications.
The long-term goal is to (i) understand mechanistically how histone modifications regulate chromatin function and 4D organisation, (ii) identify novel chromatin modifying pathways in order to discover new therapy targets and unique diagnostic or prognostic markers and (iii) move the fascinating epigenetics of the ”language of histone modifications” to a new level.
- Benabdallah, N.S., Williamson, I., Illingworth, R.S., Kane, .L, Boyle, S., Sengupta, D., Grimes, G.R., Therizols, P. Bickmore, W.A. (2019), Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation. Mol Cell. 76, 473-484
- Di Cerbo, V., Mohn, F., Ryan, D., Montellier, E., Kacem, S., Tropberger, P., Kallis, E., Holzner, M., Horner, L., Feldmann, A., Richter, F., Bannister, A.J., Mittler, G., Michaelis, J., Khochbin, S., Feil, R., Schübeler, D., Owen-Hughes, T., Daujat, S. and Schneider R. (2014) Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription eLIFe, Mar 25;3:e01632.
- Kebede, A.F, Nieborak, A., Zorro Shahidian, L., Le Gras, S., Richter, F., Aguilar Gomez, D., Baltissen, M.P., Meszaros, G., Magliarelli, H., Widmann, D. Margueron, R., Colomé-Tatché, M., Ricci, R., Daujat, S., Vermeulen, M., Mittler, G., and Schneider , R.,(2017) Histone propionylation is a novel mark of active chromatin Nature Structural and Molecular Biology, 12, 1048-1056.
- Pradeepa, M.M., Grimes, G.R., Kumar, Y., Olley, G., Taylor, G.C.A., Schneider, R. and Bickmore, W.A. (2016) Histone H3 globular domain acetylation identifies novel enhancers. Nat Genetics 48, 681-6.
- Tropberger, P., Pott, S., Keller, .C., Kamieniarz, K., Caron, M., Richter, F., Mittler, G., Liu, E.T., Bühler, M., Margueron, R., and Schneider, R. (2013) Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer. Cell, 152, 859-872