contains code and data accompanying
Computational modeling reveals cell-cycle dependent kinetics of H4K20 methylation states during Xenopus embryogenesis
Lea Schuh1,2, Carolin Loos1,2,3,4, Daniil Pokrovsky5, Axel Imhof5, Ralph A.W. Rupp5, Carsten Marr1,*
1Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, 85764, Germany
2Department of Mathematics, Technical University of Munich, Garching, 85748, Germany
3Ragon Institute of MGH, Harvard, MIT, Cambridge, MA 02139, USA
4Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
5Department of Molecular Biology, Ludwig-Maximilians-Universität München, Planegg-Martinsried, 82152, Germany
*carsten.marr@helmholtz-muenchen.de
DNA replication during cell division leads to dilution of histone modifications and can thus affect chromatin-mediated gene regulation, raising the question of how the cell-cycle shapes the histone modification landscape, particularly during embryogenesis. We tackled this problem by manipulating the cell-cycle during early Xenopus laevis embryogenesis and analyzing in vivo histone H4K20 methylation kinetics. The global distribution of un-, mono- di- and tri-methylated histone H4K20 was measured by mass spectrometry in normal and cell-cycle arrested embryos over time. Using multi-start maximum likelihood optimization and quantitative model selection, we found that three specific biological methylation rate constants were required to explain the measured H4K20 methylation state kinetics. While demethylation is essential for regulating H4K20 methylation kinetics in non-cycling cells, demethylation is very likely dispensable in rapidly dividing cells of early embryos, suggesting that cell-cycle mediated dilution of H4K20 methylation is an essential regulatory component for shaping its epigenetic landscape during early development.
Required software and toolboxes:
- MATLAB (R2017a)
- AMICI version 0.10.4, for model definition and model simulations
- [PESTO](https://github.com/ICB-DCM/PESTO version 1.1.9 for parameter estimation and MCMC sampling
Both toolboxes, AMICI and PESTO, can be found in the folder tools but need to be unzipped. Additionally, AMICI creates '.mex' files and requires a C/C++ compiler. The analysis was performed on a macOS Catalina version 10.15.3.
Here you can find the list of folders
There are mainly two important scripts (i) for the analysis summarized in master_script.m (see Workflow) and (ii) for the figures summarized in figure_script.m (see Figures).
The H4K20 methylation proportions of both mock and HUA over time can be found in the file data/H4K20states.xlsx. Until the original data set will be published we will provide dummy data in data/H4K20states_dummy.xlsx. Upon publication of the data we will upload the the true data here. The H4K20me proportions of the morpholino knock-downs of the di- and tri-methyltransferases SUV4-20H1/2 are given in data/H4K20MO.xlsx. The doubling times of cells during Xenopus embryogenesis found in literature are summarized in data/DTdata.xlsx. The corresponding import scripts can be found in the same folder. The images of mock and HUA embryos corresponding to the different developmental stages (Figure 1A) can be found in images.
The workflow to the whole manuscript can be found in the script master_script.m. The model files for the compilation with AMICI can be found in the folder syms, the compiled model files in the folder simulation.
figure_script.m recreates all figure panels of the paper. The created figure files are saved to and can be found in the folder figures.
All estimated parameter sets of the optimization and the MCMC sampling results of selected models can be found in the folder parameters. Summaries of the average doubling times of all mock models and the BIC values of all mock and HUA models as well as the processed MCMC samples can be found in the folder results.
The summary of all model optimizations (rank, delta BIC, BIC, model ID adn potentially the average doubling time) can be found in HistonesXenopus_results.xlsx.