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      Analysis of the transcriptional logic governing differential spatial expression in Hh target genes

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      PLoS ONE
      Public Library of Science

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          Abstract

          This work provides theoretical tools to analyse the transcriptional effects of certain biochemical mechanisms (i.e. affinity and cooperativity) that have been proposed in previous literature to explain the proper spatial expression of Hedgehog target genes involved in Drosophila development. Specifically we have focused on the expression of decapentaplegic, wingless, stripe and patched. The transcription of these genes is believed to be controlled by enhancer modules able to interpret opposing gradients of the activator and repressor forms of the transcription factor Cubitus interruptus (Ci). This study is based on a thermodynamic approach, which provides expression rates for these genes. These expression rates are controlled by transcription factors which are competing and cooperating for common binding sites. We have made mathematical representations of the different expression rates which depend on multiple factors and variables. The expressions obtained with the model have been refined to produce simpler equivalent formulae which allow for their mathematical analysis. Thanks to this, we can evaluate the correlation between the different interactions involved in transcription and the biological features observed at tissular level. These mathematical models can be applied to other morphogenes to help understand the complex transcriptional logic of opposing activator and repressor gradients.

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          Transcriptional regulation by the numbers: models.

          The expression of genes is regularly characterized with respect to how much, how fast, when and where. Such quantitative data demands quantitative models. Thermodynamic models are based on the assumption that the level of gene expression is proportional to the equilibrium probability that RNA polymerase (RNAP) is bound to the promoter of interest. Statistical mechanics provides a framework for computing these probabilities. Within this framework, interactions of activators, repressors, helper molecules and RNAP are described by a single function, the "regulation factor". This analysis culminates in an expression for the probability of RNA polymerase binding at the promoter of interest as a function of the number of regulatory proteins in the cell.
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            Transcriptional activation by recruitment.

            The recruitment model for gene activation stipulates that an activator works by bringing the transcriptional machinery to the DNA. Recent experiments in bacteria and yeast indicate that many genes can be activated by this mechanism. These findings have implications for our understanding of the nature of activating regions and their targets, and for the role of histones in gene regulation.
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              Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins.

              Members of the Hedgehog (Hh) family of secreted proteins have been identified recently as key signaling molecules that regulate a variety of inductive interactions central to the development of both Drosophila and vertebrates. Despite their widespread importance, the way in which Hh signals are transduced inside the cell remains poorly understood. The best candidate for a transcription factor that mediates Hh signaling in Drosophila is the product of the cubitus interruptus (ci) gene, a zinc finger protein that exhibits significant homology to protein products of the vertebrate GLI gene family. Here, we show that elevated levels of Ci are sufficient to activate patched (ptc) and other hh target genes, even in the absence of hh activity. We also show that Ci can function as a transcriptional activator in yeast and demonstrate that the zinc finger domain of the protein is sufficient for its target specificity. Finally, we identify sequences in the promoter region of the ptc gene, a primary target of Hh signaling, that are identical to the consensus-binding sequence of the GLI protein and are required for reporter gene expression in response to Hh activity. Taken together, our results strongly support the role for Ci as the transcriptional activator that mediates hh signaling.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2019
                7 January 2019
                : 14
                : 1
                : e0209349
                Affiliations
                [1 ] Applied Mathematics Department, University of Granada, Granada, Spain
                [2 ] Excellence Research Unit “Modeling Nature” (MNat), University of Granada, Granada, Spain
                Fred Hutchinson Cancer Research Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-8123-3997
                Article
                PONE-D-18-16852
                10.1371/journal.pone.0209349
                6322776
                30615641
                9dc9e11e-ec99-462e-9d03-cca5b76b14c0
                © 2019 Cambón, Sánchez

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 June 2018
                : 4 December 2018
                Page count
                Figures: 3, Tables: 1, Pages: 25
                Funding
                Funded by: Ministerio de Economía, Industria y Competitividad, Gobierno de España (ES)
                Award ID: MTM2014-53406-R
                Award Recipient :
                Funded by: Ministerio de Economía, Industria y Competitividad, Gobierno de España (ES)
                Award ID: MTM2014-53406-R
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002878, Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía;
                Award ID: FQM 954
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002878, Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía;
                Award ID: FQM 954
                Award Recipient :
                Funded by: Ministerio de Economía, Industria y Competitividad, Gobierno de España (ES)
                Award ID: FPI2015/074837
                Award Recipient :
                This work has been partially supported by: the Ministerio de Economía y competitividad (Spain Government) research grants numbers MTM2014-53406-R and FPI2015/074837 http://www.mineco.gob.es/portal/site/mineco/ and the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (Andalucía Government) Project FQM 954, https://www.juntadeandalucia.es/organismos/empleoempresaycomercio.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Genetics
                Gene expression
                DNA transcription
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Transcription Factors
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcription Factors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Regulatory Proteins
                Transcription Factors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Hedgehog Signaling
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Polymerases
                RNA polymerase
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Model Organisms
                Drosophila Melanogaster
                Research and Analysis Methods
                Model Organisms
                Drosophila Melanogaster
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Drosophila Melanogaster
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster
                Biology and Life Sciences
                Developmental Biology
                Morphogenesis
                Imaginal Discs
                Physical Sciences
                Physics
                Thermodynamics
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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