{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:28:56Z","timestamp":1790713736210,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"30","license":[{"start":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T00:00:00Z","timestamp":1562630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["091580"],"award-info":[{"award-number":["091580"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["203149"],"award-info":[{"award-number":["203149"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["107930"],"award-info":[{"award-number":["107930"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["099841"],"award-info":[{"award-number":["099841"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rett Syndrome Research Trust","award":["None"],"award-info":[{"award-number":["None"]}]},{"DOI":"10.13039\/501100000332","name":"Royal Society of Edinburgh","doi-asserted-by":"publisher","award":["Not available"],"award-info":[{"award-number":["Not available"]}],"id":[{"id":"10.13039\/501100000332","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,7,23]]},"abstract":"<jats:p>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 \u201cslow sites\u201d 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.<\/jats:p>","DOI":"10.1073\/pnas.1903549116","type":"journal-article","created":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T17:05:54Z","timestamp":1562691954000},"page":"14995-15000","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":59,"title":["Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic"],"prefix":"10.1073","volume":"116","author":[{"given":"Justyna","family":"Cholewa-Waclaw","sequence":"first","affiliation":[{"name":"The Wellcome Centre for Cell Biology, University of Edinburgh, EH9 3BF Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Shah","sequence":"additional","affiliation":[{"name":"The Wellcome Centre for Cell Biology, University of Edinburgh, EH9 3BF Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Webb","sequence":"additional","affiliation":[{"name":"The Wellcome Centre for Cell Biology, University of Edinburgh, EH9 3BF Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashyap","family":"Chhatbar","sequence":"additional","affiliation":[{"name":"The Wellcome Centre for Cell Biology, University of Edinburgh, EH9 3BF Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Ramsahoye","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, EH4 2XU Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Pusch","sequence":"additional","affiliation":[{"name":"Center for Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Yu","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Greulich","sequence":"additional","affiliation":[{"name":"Mathematical Sciences, University of Southampton, SO17 1BJ Southampton, United Kingdom;"},{"name":"Institute for Life Sciences, University of Southampton, SO17 1BJ Southampton, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5355-7994","authenticated-orcid":false,"given":"Bartlomiej","family":"Waclaw","sequence":"additional","affiliation":[{"name":"School of Physics and Astronomy, University of Edinburgh, EH9 3FD Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian P.","family":"Bird","sequence":"additional","affiliation":[{"name":"The Wellcome Centre for Cell Biology, University of Edinburgh, EH9 3BF Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,7,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.08.026"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2017.02.013"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.396106"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/21541264.2017.1285851"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3953"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.11.6538"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90610-O"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.01.030"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33184"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81887-5"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/30764"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/85899"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3434"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006793"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1618737114"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14319"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07255.x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2688"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/21.21.4886"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704304200"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2008.31"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.07.021"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1088\/1751-8113\/40\/46\/R01"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0370-1573(98)00006-4"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2470"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.7.487"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1700731114"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1138389"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.10011.1"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.04.027"},{"key":"e_1_3_4_32_2","volume-title":"ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide","author":"Buenrostro J. D.","year":"2015","unstructured":"J. D. Buenrostro, B. Wu, H. Y. Chang, W. J. Greenleaf, ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide (John Wiley & Sons, Inc., Hoboken, NJ, 2015)."},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr167"},{"key":"e_1_3_4_35_2","unstructured":"J. Cholewa-Waclaw . Study of MeCP2 in LUHMES-derived neurons. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE125660. Deposited on 25 January 2019."},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2017.04.009"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq128"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-199"},{"key":"e_1_3_4_39_2","unstructured":"B. Waclaw . Supplementary data for the manuscript \u201cQuantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic.\u201d Edinburgh DataShare University of Edinburgh. https:\/\/doi.org\/10.7488\/ds\/2568. Deposited 7 June 2019."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1903549116","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1903549116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T15:43:23Z","timestamp":1654616603000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1903549116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,9]]},"references-count":39,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2019,7,23]]}},"alternative-id":["10.1073\/pnas.1903549116"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1903549116","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/391904","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,9]]},"assertion":[{"value":"2019-07-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}