PT  - JOURNAL ARTICLE
AU  - Justyna Cholewa-Waclaw
AU  - Ruth Shah
AU  - Shaun Webb
AU  - Kashyap Chhatbar
AU  - Bernard Ramsahoye
AU  - Oliver Pusch
AU  - Miao Yu
AU  - Philip Greulich
AU  - Bartlomiej Waclaw
AU  - Adrian Bird
TI  - Mathematical modelling reveals how MeCP2 restrains transcriptional elongation in human neurons
AID  - 10.1101/391904
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 391904
4099  - http://biorxiv.org/content/early/2018/08/14/391904.short
4100  - http://biorxiv.org/content/early/2018/08/14/391904.full
AB  - Gene expression patterns depend on the interaction of diverse transcription factors with their target genes. While many factors have a restricted number of targets, some appear to affect transcription globally. An example of the latter is MeCP2; an abundant chromatin-associated protein that is mutated in the neurological disorder Rett Syndrome. To understand how MeCP2 affects transcription, we integrated mathematical modelling with quantitative experimental analysis of human neurons expressing graded levels of MeCP2. We first used a model of MeCP2-DNA binding to demonstrate that changes in gene expression reflect MeCP2 density downstream of transcription initiation. We then tested five biologically plausible hypotheses for the effect of MeCP2 on transcription. The only model compatible with the data involved slowing down of RNA polymerase II by MeCP2, causing reduced transcript output due to polymerase queueing. Our general approach may prove fruitful in deciphering the mechanisms by which other global regulators choreograph gene expression.