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

Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic
Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic
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.
0027-8424
Cholewa-Waclaw, Justyna
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Shah, Ruth
e4eb5fed-fd4e-449a-bd24-938b6b3984a1
Webb, Shaun
eb3f395b-329b-4706-8cb7-eb4251bdce03
Chhatbar, Kahsyap
b0a70e85-682a-4ff0-baff-25c2e804b6ae
Ramsahoye, Bernard
61b43e97-cf7a-4154-afe5-e4d5e438b072
Pusch, Oliver
f6a605e6-aed3-44cd-91ab-96a95b7cd78e
Yu, Miao
864089cc-361f-42d5-b297-9be22ccad828
Greulich, Philip
65da32ad-a73a-435a-86e0-e171437430a9
Waclaw, Bartlomiej
caa8d9c8-625a-4b49-98b5-a319cec21742
Bird, Adrian P.
652e98cc-b9c2-45a8-8c4b-f28449750190
Cholewa-Waclaw, Justyna
9452d1ef-ad40-4793-831d-344eab0ae742
Shah, Ruth
e4eb5fed-fd4e-449a-bd24-938b6b3984a1
Webb, Shaun
eb3f395b-329b-4706-8cb7-eb4251bdce03
Chhatbar, Kahsyap
b0a70e85-682a-4ff0-baff-25c2e804b6ae
Ramsahoye, Bernard
61b43e97-cf7a-4154-afe5-e4d5e438b072
Pusch, Oliver
f6a605e6-aed3-44cd-91ab-96a95b7cd78e
Yu, Miao
864089cc-361f-42d5-b297-9be22ccad828
Greulich, Philip
65da32ad-a73a-435a-86e0-e171437430a9
Waclaw, Bartlomiej
caa8d9c8-625a-4b49-98b5-a319cec21742
Bird, Adrian P.
652e98cc-b9c2-45a8-8c4b-f28449750190

Cholewa-Waclaw, Justyna, Shah, Ruth, Webb, Shaun, Chhatbar, Kahsyap, Ramsahoye, Bernard, Pusch, Oliver, Yu, Miao, Greulich, Philip, Waclaw, Bartlomiej and Bird, Adrian P. (2019) Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic. Proceedings of the National Academy of Sciences. (doi:10.1073/pnas.1903549116).

Record type: Article

Abstract

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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Accepted/In Press date: 19 June 2019
Published date: 9 July 2019

Identifiers

Local EPrints ID: 432361
URI: http://eprints.soton.ac.uk/id/eprint/432361
ISSN: 0027-8424
PURE UUID: cf6c7045-f9df-46c6-aed4-1c2d326b3991
ORCID for Philip Greulich: ORCID iD orcid.org/0000-0001-5247-6738

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Date deposited: 11 Jul 2019 16:30
Last modified: 26 Nov 2019 05:01

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Contributors

Author: Justyna Cholewa-Waclaw
Author: Ruth Shah
Author: Shaun Webb
Author: Kahsyap Chhatbar
Author: Bernard Ramsahoye
Author: Oliver Pusch
Author: Miao Yu
Author: Philip Greulich ORCID iD
Author: Bartlomiej Waclaw
Author: Adrian P. Bird

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