Specificity, propagation, and memory of pericentric heterochromatin

• Published in: Molecular systems biology 2014-08, Vol.10 (8), p.746-n/a
• Main Authors: Müller‐Ott, Katharina, Erdel, Fabian, Matveeva, Anna, Mallm, Jan‐Philipp, Rademacher, Anne, Hahn, Matthias, Bauer, Caroline, Zhang, Qin, Kaltofen, Sabine, Schotta, Gunnar, Höfer, Thomas, Rippe, Karsten
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Cell cycle; Cell division; Cell Nucleus - genetics; Cell Nucleus - metabolism; Chromatin; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Deoxyribonucleic acid; DNA; DNA Methylation; Domains; EMBO09; EMBO33; Epigenesis, Genetic; Epigenetics; Feedback; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; FRAP/FCS; Gene Silencing; Genetic Markers; Genomes; Heterochromatin; Heterochromatin - genetics; Heterochromatin - metabolism; heterochromatin protein 1; Histone H3; histone methylation; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - genetics; Histones - metabolism; Immobilization; Lysine; Mathematical models; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Microscopy; Mitosis; NIH 3T3 Cells; Nucleation; Ordinary differential equations; pericentric heterochromatin; Propagation; Protein Interaction Domains and Motifs; protein network; Proteins; Repetitive Sequences, Nucleic Acid; Robustness (mathematics); Sensitivity and Specificity
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20145377

The cell establishes heritable patterns of active and silenced chromatin via interacting factors that set, remove, and read epigenetic marks. To understand how the underlying networks operate, we have dissected transcriptional silencing in pericentric heterochromatin (PCH) of mouse fibroblasts. We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in living cells and found that stably bound complexes of the histone methyltransferase SUV39H1/2 demarcate the PCH state. From the experimental data, we developed a predictive mathematical model that explains how chromatin‐bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin dynamics. This “nucleation and looping” mechanism is particularly robust toward transient perturbations and stably maintains the PCH state. These features make it an attractive model for establishing functional epigenetic domains throughout the genome based on the localized immobilization of chromatin‐modifying enzymes. Synopsis A comprehensive analysis of the epigenetic network that silences pericentric heterochromatin (PCH) transcription in mouse fibroblasts is presented. The resulting quantitative model explains the spatial extension, stability and propagation of histone modification domains. A quantitative map of the abundance and interactions of 16 PCH factors is generated by fluorescence microscopy/spectroscopy and ChIP‐seq. A predictive mathematical model, based on the quantitative data, explains how the silenced PCH state is maintained and transmitted through the cell cycle. A “nucleation and looping” mechanism is proposed, in which chromatin‐bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated H3K9me3 modifications via chromatin dynamics. Graphical Abstract A comprehensive analysis of the epigenetic network that silences pericentric heterochromatin (PCH) transcription in mouse fibroblasts is presented. The resulting quantitative model explains the spatial extension, stability and propagation of histone modification domains.