A quantitative validated model reveals two phases of transcriptional regulation for the gap gene giant in Drosophila

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• dc.contributor.author Hoermann, Astrid, 1981-ca
• dc.contributor.author Cicin Sain, Damjanca
• dc.contributor.author Jaeger, Johannes, 1973-ca
• dc.date.accessioned 2016-06-06T14:25:21Z
• dc.date.available 2016-06-06T14:25:21Z
• dc.date.issued 2016
• dc.description.abstract Understanding eukaryotic transcriptional regulation and its role in development and pattern formation is one of the big challenges in biology today. Most attempts at tackling this problem either focus on the molecular details of transcription factor binding, or aim at genome-wide prediction of expression patterns from sequence through bioinformatics and mathematical modelling. Here we bridge the gap between these two complementary approaches by providing an integrative model of cis-regulatory elements governing the expression of the gap gene giant (gt) in the blastoderm embryo of Drosophila melanogaster. We use a reverse-engineering method, where mathematical models are fit to quantitative spatio-temporal reporter gene expression data to infer the regulatory mechanisms underlying gt expression in its anterior and posterior domains. These models are validated through prediction of gene expression in mutant backgrounds. A detailed analysis of our data and models reveals that gt is regulated by domain-specific CREs at early stages, while a late element drives expression in both the anterior and the posterior domains. Initial gt expression depends exclusively on inputs from maternal factors. Later, gap gene cross-repression and gt auto-activation become increasingly important. We show that auto-regulation creates a positive feedback, which mediates the transition from early to late stages of regulation. We confirm the existence and role of gt auto-activation through targeted mutagenesis of Gt transcription factor binding sites. In summary, our analysis provides a comprehensive picture of spatio-temporal gene regulation by different interacting enhancer elements for an important developmental regulator.ca
• dc.description.sponsorship A.H. received funding from the La Caixa Foundation to conduct her PhD project at the CRG. The laboratory of J.J. is funded by the MEC-EMBL agreement for the EMBL/CRG Research Unit in Systems Biology. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement FP7-KBBE-2011-5/289434 (BioPreDyn), by Grant 153 (MOPDEV) of the ERANet: ComplexityNET programme, by AGAUR SGR Grant 406, as well as grants BFU2009-10184 and BFU2012-33775 from the Spanish Ministry of the Economy and Competitiveness (MINECO, formerly MICINN). The Centre for Genomic Regulation (CRG) acknowledges support from MINECO, 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Hoermann A, Cicin-Sain D, Jaeger J. A quantitative validated model reveals two phases of transcriptional regulation for the gap gene giant in Drosophila. Developmental Biology. 2016;411(2):325-38. DOI: 10.1016/j.ydbio.2016.01.005ca
• dc.identifier.doi http://dx.doi.org/10.1016/j.ydbio.2016.01.005
• dc.identifier.issn 0012-1606
• dc.identifier.uri http://hdl.handle.net/10230/26857
• dc.language.iso engca
• dc.publisher Elsevierca
• dc.relation.ispartof Developmental Biology. 2016;411(2):325-38
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2012-33775
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2009-10184
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/289434
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SEV2012-0208
• dc.rights © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/ca
• dc.subject.keyword Cis-regulatory elements (CREs)
• dc.subject.keyword Drosophila melanogaster
• dc.subject.keyword Mathematical modelling
• dc.subject.keyword Reverse engineering
• dc.subject.keyword Auto-activation
• dc.subject.keyword Gene expression dynamics
• dc.subject.other Drosòfilaca
• dc.title A quantitative validated model reveals two phases of transcriptional regulation for the gap gene giant in Drosophilaca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca