Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 30; pp. 14995 - 15000
• Main Authors: Cholewa-Waclaw, Justyna, Shah, Ruth, Webb, Shaun, Chhatbar, Kashyap, Ramsahoye, Bernard, Pusch, Oliver, Yu, Miao, Greulich, Philip, Waclaw, Bartlomiej, Bird, Adrian P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.07.2019
• Subjects: Animals; Biological Sciences; Cell Line; Deoxyribonucleic acid; DNA; DNA Methylation; DNA-directed RNA polymerase; Gene expression; Gene regulation; Genomes; Mathematical models; MeCP2 protein; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Models, Theoretical; Neurological diseases; Protein Binding; Proteins; Rett syndrome; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; RNA Polymerase II - metabolism; Shock waves; Transcription Elongation, Genetic; Transcription factors; Transcription initiation; Transcription Initiation, Genetic; Transcriptional Activation; Transportation models; DNA methylation; MeCP2; mathematical modelling; gene regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1903549116

Patterns of gene expression are primarily determined by proteins that locally enhance or repress transcription. While many transcription factors target a restricted number of genes, others appear to modulate transcription levels globally. An example is MeCP2, an abundant methylated-DNA binding protein that is mutated in the neurological disorder Rett syndrome. Despite much research, the molecular mechanism by which MeCP2 regulates gene expression is not fully resolved. Here, we integrate quantitative, multidimensional experimental analysis and mathematical modeling to indicate that MeCP2 is a global transcriptional regulator whose binding to DNA creates “slow sites” in gene bodies. We hypothesize that waves of slowed-down RNA polymerase II formed behind these sites travel backward and indirectly affect initiation, reminiscent of defect-induced shockwaves in nonequilibrium physics transport models. This mechanism differs from conventional gene-regulation mechanisms, which often involve direct modulation of transcription initiation. Our findings point to a genome-wide function of DNA methylation that may account for the reversibility of Rett syndrome in mice. Moreover, our combined theoretical and experimental approach provides a general method for understanding how global gene-expression patterns are choreographed.