RT Journal Article
SR Electronic
T1 Mathematical modelling reveals how MeCP2 restrains transcriptional elongation in human neurons
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 391904
DO 10.1101/391904
A1 Justyna Cholewa-Waclaw
A1 Ruth Shah
A1 Shaun Webb
A1 Kashyap Chhatbar
A1 Bernard Ramsahoye
A1 Oliver Pusch
A1 Miao Yu
A1 Philip Greulich
A1 Bartlomiej Waclaw
A1 Adrian Bird
YR 2018
UL http://biorxiv.org/content/early/2018/08/14/391904.abstract
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.