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

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Original languageEnglish
JournalProceedings of the National Academy of Sciences
Publication statusPublished - 9 Jul 2019


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 modelling
to indicate that MeCP2 is a novel type of global transcriptional regulator whose binding to DNA creates "slow sites" in gene bodies. We hypothesise that waves of slowed-down RNA polymerase II formed behind these sites travel backward and indirectly affect initiation, reminiscent of defect-induced shock waves in
non-equilibrium 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.

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