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Throwing a loop to silence gene expression

Cells attach epigenetic signals to their genome to select which part of their genetic information is used. In our recent study a comprehensive analysis was conducted to dissect the epigenetic network that silences pericentric heterochromatin (PCH) transcription in mouse fibroblasts. We acquired a quantitative map of the abundance and interactions of 16 PCH factors by fluorescence microscopy/spectroscopy and ChIP-seq. Based on the quantitative data, we developed a predictive mathematical model, referred to as the 'nucleation and looping' mechanism. It explains the spatial extension and maintenance of the H3K9me3 histone modification as a hallmark of the silenced PCH state. The work has now been published in the journal Molecular Systems Biology.

Deciphering the cell’s ‘epigenetic code’ is a challenging task: Hundreds of proteins in the cell are linked in large networks to ‘write’, ‘erase’ or ‘read’ about 140 different chemical modifications of histone proteins and DNA that have been identified so far. Understanding how epigenetic regulation operates for a specific part of the genome thus requires an integrative approach that considers the connections between different factors. Together with our colleagues from the groups of Thomas Höfer at the DKFZ and Gunnar Schotta at the LMU Munich, the Rippe team has conducted a comprehensive analysis of a prototypic epigenetic network. We studied how interactions of protein and chromatin conspire to silence satellite repeats in mouse pericentric heterochromatin by trimethylation of lysine 9 of histone H3 and DNA methylation. If transcriptionally active, these repeats would make the genome instable and lead to chromosome segregation defects.

Based on maps of epigenetic signals and interactions of proteins with the genome, our study developed a mathematical model for epigenetic silencing. “The silencing mechanism we found works much like throwing a loop with a lasso to catch something”, says Katharina Müller-Ott, the first author of the study: “Several factors bind the silencing enzyme stably to certain sites in the genome. Because the DNA randomly moves around and forms transient loops, the enzyme hits other regions in the genome nearby, which then become modified and are switched off.”

 

The 'nucleation and looping' model has some similarities with cowboys throwing their lasso to catch something:  The histone methylating enzyme is stably bound to a site in the genome and interacts with distant parts via looping of the intervening DNA to distribute the epigenetic methylation signal in the environment.

Photo by Laura Wilson.

Having a quantitative description of this process at hand allows us to explain the spatial extension, stability and propagation of histone modification domains, and one can predict how the silencing network reacts in response to perturbations. These include for example changes of the abundance of proteins or inhibiting the activity of enzymes involved in methylation or acetylation with 'epigenetic' drugs. Furthermore, we are continuing to further develop and apply our model and mechanistic insight to deregulated epigenetic signaling in leukemia within the CancerEpiSys consortium. The research collaboration evaluates genome-wide maps of epigenetic signals with mathematical models to identify tumor-specific changes in cell samples from patients with blood cancer. Furthermore, the program evaluates how epigenetic signals can be used to predict therapy response and how drugs affect the epigenetic program.

The project was supported by the German Federal Ministry of Education and Research (BMBF) within the SysTec and CancerSys programs.

Müller-Ott, K., Erdel, F., Matveeva, A., Hahn, M., Mallm, J.-P., Rademacher, A., Marth, C., Zhang, Q., Kaltofen, S., Schotta, G., Höfer, T. & Rippe, K. (2014). Specificity, propagation and memory of pericentric heterochromatin. Mol. Syst. Biol. 10, 746. doi: 10.15252/msb.20145377 | Abstract | Reprint (7.4 MB)

Press release from the German Cancer Research Center (DKFZ) in English or in German

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