{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T11:25:58Z","timestamp":1776079558676,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011071","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000}}],"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:00:00Z","timestamp":1684454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSF-Simons Center","award":["DMS1763272"],"award-info":[{"award-number":["DMS1763272"]}]},{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"publisher","award":["594598"],"award-info":[{"award-number":["594598"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS1616233"],"award-info":[{"award-number":["DMS1616233"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HD095246"],"award-info":[{"award-number":["R01HD095246"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UC President\u2019s Dissertation Year Fellowship"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Enhancers are stretches of regulatory DNA that bind transcription factors (TFs) and regulate the expression of a target gene. Shadow enhancers are two or more enhancers that regulate the same target gene in space and time and are associated with most animal developmental genes. These multi-enhancer systems can drive more consistent transcription than single enhancer systems. Nevertheless, it remains unclear why shadow enhancer TF binding sites are distributed across multiple enhancers rather than within a single large enhancer. Here, we use a computational approach to study systems with varying numbers of TF binding sites and enhancers. We employ chemical reaction networks with stochastic dynamics to determine the trends in transcriptional noise and fidelity, two key performance objectives of enhancers. This reveals that while additive shadow enhancers do not differ in noise and fidelity from their single enhancer counterparts, sub- and superadditive shadow enhancers have noise and fidelity trade-offs not available to single enhancers. We also use our computational approach to compare the duplication and splitting of a single enhancer as mechanisms for the generation of shadow enhancers and find that the duplication of enhancers can decrease noise and increase fidelity, although at the metabolic cost of increased RNA production. A saturation mechanism for enhancer interactions similarly improves on both of these metrics. Taken together, this work highlights that shadow enhancer systems may exist for several reasons: genetic drift or the tuning of key functions of enhancers, including transcription fidelity, noise and output.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011071","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T17:40:58Z","timestamp":1684518058000},"page":"e1011071","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Shadow enhancers mediate trade-offs between transcriptional noise and fidelity"],"prefix":"10.1371","volume":"19","author":[{"given":"Alvaro","family":"Fletcher","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4491-5715","authenticated-orcid":true,"given":"Zeba","family":"Wunderlich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8908-9539","authenticated-orcid":true,"given":"German","family":"Enciso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"key":"pcbi.1011071.ref001","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1126\/science.1160631","article-title":"Shadow enhancers as a source of evolutionary novelty","volume":"321","author":"JW Hong","year":"2008","journal-title":"Science"},{"key":"pcbi.1011071.ref002","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.neuron.2015.07.031","article-title":"Regulatory logic of pan-neuronal gene expression in C. elegans","volume":"87","author":"N Stefanakis","year":"2015","journal-title":"Neuron"},{"key":"pcbi.1011071.ref003","doi-asserted-by":"crossref","first-page":"e1007581","DOI":"10.1371\/journal.pgen.1007581","article-title":"Cooperation, cis-interactions, versatility and evolutionary plasticity of multiple cis-acting elements underlie krox20 hindbrain regulation","volume":"14","author":"P Torbey","year":"2018","journal-title":"PLOS Genetics"},{"key":"pcbi.1011071.ref004","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1242\/dev.02239","article-title":"A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers","volume":"133","author":"Y Jeong","year":"2006","journal-title":"Development (Cambridge, England)"},{"key":"pcbi.1011071.ref005","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.ydbio.2009.12.030","article-title":"Distinct enhancers at the Pax3 locus can function redundantly to regulate neural tube and neural crest expressions","volume":"339","author":"KR Degenhardt","year":"2010","journal-title":"Developmental Biology"},{"key":"pcbi.1011071.ref006","doi-asserted-by":"crossref","first-page":"26278","DOI":"10.1074\/jbc.270.44.26278","article-title":"Evolutionary duplication of a hepatic control region in the human apolipoprotein E gene locus. Identification of a second region that confers high level and liver-specific expression of the human apolipoprotein E gene in transgenic mice","volume":"270","author":"CM Allan","year":"1995","journal-title":"The Journal of Biological Chemistry"},{"key":"pcbi.1011071.ref007","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1182\/blood-2002-04-1104","article-title":"Locus control regions","volume":"100","author":"Q Li","year":"2002","journal-title":"Blood"},{"key":"pcbi.1011071.ref008","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/j.cub.2010.07.043","article-title":"Shadow enhancers foster robustness of Drosophila gastrulation","volume":"20","author":"MW Perry","year":"2010","journal-title":"Current Biology"},{"key":"pcbi.1011071.ref009","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nature09158","article-title":"Phenotypic robustness conferred by apparently redundant transcriptional enhancers","volume":"466","author":"N Frankel","year":"2010","journal-title":"Nature"},{"key":"pcbi.1011071.ref010","doi-asserted-by":"crossref","first-page":"e1006441","DOI":"10.1371\/journal.pgen.1006441","article-title":"The gene regulatory network of lens induction is wired through meis-dependent shadow enhancers of Pax6","volume":"12","author":"B Antosova","year":"2016","journal-title":"PLoS genetics"},{"key":"pcbi.1011071.ref011","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nature25461","article-title":"Enhancer redundancy provides phenotypic robustness in mammalian development","volume":"554","author":"M Osterwalder","year":"2018","journal-title":"Nature"},{"key":"pcbi.1011071.ref012","first-page":"1","article-title":"Enhancer redundancy in development and disease","author":"EZ Kvon","year":"2021","journal-title":"Nature Reviews Genetics"},{"key":"pcbi.1011071.ref013","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cub.2015.11.034","article-title":"Shadow enhancers are pervasive 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