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Eric H. Davidson - One of the best experts on this subject based on the ideXlab platform.

  • Caught in the evolutionary act: precise Cis-Regulatory basis of difference in the organization of gene networks of sea stars and sea urchins.
    2018
    Co-Authors: Veronica F. Hinman, Albert Nguyen, Eric H. Davidson
    Abstract:

    The regulatory control of otxbeta1/2 in the sea urchin Strongylocentrotus purpuratus and the sea star Asterina miniata provides an exceptional opportunity to determine the genomic basis of evolutionary change in gene regulatory network (GRN) architectures. Network perturbation analyses in both taxa show that Otx regulates the transcription factors gatae and krox/blimp1 and both of these transcription factors also feed back and regulate otx. The otx gene also autoregulates. This three way interaction is an example of a GRN kernel. It has been conserved for 500 million years since these two taxa last shared a common ancestor. Amid this high level of conservation we show here one significant regulatory change. Tbrain is required for correct otxbeta1/2 expression in the sea star but not in the sea urchin. In sea urchin, tbrain is not co-expressed with otxbeta1/2 and instead has an essential role in specification of the embryonic skeleton. Tbrain in these echinoderms is thus a perfect example of an orthologous gene co-opted for entirely different developmental processes. We isolate and test the sea star otxbeta1/2 Cis-Regulatory Module and demonstrate functional binding sites for each of the predicted inputs, including Tbrain. We compare it to the logic processing operating in the sea urchin otxbeta1/2 Cis-Regulatory Module and present an evolutionary scenario of the change in Tbrain dependence. Finally, inter-specific gene transfer experiments confirm this scenario and demonstrate evolution occurring at the level of sequence changes to the Cis-Regulatory Module.

  • Chapter III Regulation of Spblimp1/krox1a: an alternatively transcribed isoform expressed in the mid and hindgut of the sea urchin gastrula.
    2014
    Co-Authors: Carolina B Livi, Eric H. Davidson
    Abstract:

    “Regulation of Spblimp1/krox1a: an alternatively transcribed isoform expressed in the mid and hindgut of the sea urchin gastrula, ” Copyright (2006), with permission from Elsevier. III-3 The sea urchin regulatory gene Spblimp1/krox produces alternatively transcribed and spliced isoforms, 1a and 1b, which have different temporal and spatial patterns of expression. Here we describe a Cis-Regulatory Module that controls the expression of the 1a splice form in the midgut and hindgut at the beginning of gastrulation. Conserved sequence patches revealed by a comparison of the blimp1/krox locus in Strongylocentrotus purpuratus and Lytechinus variegatus genomes were tested by gene transfer, in association with GFP or CAT reporter genes. An expression construct containing a conserved sequence patch immediately 5 ' of exon 1a included the transcription initiation site for blimp1/krox1a. This construct displays specific mid and hindgut expression, indicating that these are the locations of endogenous blimp1/krox1a transcription during the gastrula stage. Its sequence contains binding sites for Brn1/2/4, Otx, and Blimp1/Krox itself, as predicted in a prior regulatory network analysis

  • cis regulatory control of the nodal gene initiator of the sea urchin oral ectoderm gene network
    Developmental Biology, 2007
    Co-Authors: Jongmin Nam, Pei Yun Lee, Anthony J Robertson, James A Coffman, Eric H. Davidson
    Abstract:

    Expression of the nodal gene initiates the gene regulatory network which establishes the transcriptional specification of the oral ectoderm in the sea urchin embryo. This gene encodes a TGFβ ligand, and in Strongylocentrotus purpuratus its transcription is activated in the presumptive oral ectoderm at about the 30-cell stage. Thereafter Nodal signaling occurs among all cells of the oral ectoderm territory, and nodal expression is required for expression of oral ectoderm regulatory genes. The Cis-Regulatory system of the nodal gene transduces anisotropically distributed cytoplasmic cues that distinguish the future oral and aboral domains of the early embryo. Here we establish the genomic basis for the initiation and maintenance of nodal gene expression in the oral ectoderm. Functional Cis-Regulatory control Modules of the nodal gene were identified by interspecific sequence conservation. A 5′ Cis-Regulatory Module functions both to initiate expression of the nodal gene and to maintain its expression by means of feedback input from the Nodal signal transduction system. These functions are mediated respectively by target sites for bZIP transcription factors, and by SMAD target sites. At least one SMAD site is also needed for the initiation of expression. An intron Module also contains SMAD sites which respond to Nodal feedback, and in addition acts to repress vegetal expression. These observations explain the main features of nodal expression in the oral ectoderm: since the activity of bZIP factors is redox sensitive, and the initial polarization of oral vs. aboral fate is manifested in a redox differential, the bZIP sites account for the activation of nodal on the oral side; and since the immediate early signal transduction response factors for Nodal are SMAD factors, the SMAD sites account for the feedback maintenance of nodal gene expression.

  • Exclusive developmental functions of gatae Cis-Regulatory Modules in the Strongylocentrorus purpuratus embryo
    Developmental biology, 2007
    Co-Authors: Pei Yun Lee, Jongmin Nam, Eric H. Davidson
    Abstract:

    The gatae gene of Strongylocentrotus purpuratus is orthologous to vertebrate gata-4,5,6 genes. This gene is expressed in the endomesoderm in the blastula and later the gut of the embryo, and is required for normal development. A gatae BAC containing a GFP reporter knocked into exon one of the gene was able to reproduce all aspects of endogenous gatae expression in the embryo. To identify putative gatae Cis-Regulatory Modules we carried out an interspecific sequence conservation analysis with respect to a Lytechinus variegatus gatae BAC, which revealed 25 conserved non-coding sequence patches. These were individually tested in gene transfer experiments, and two Modules capable of driving localized reporter expression in the embryo were identified. Module 10 produces early expression in mesoderm and endoderm cells up to the early gastrula stage, while Module 24 generates late endodermal expression at gastrula and pluteus stages. Module 10 was then deleted from the gatae BAC by reciprocal recombination, resulting in total loss of reporter expression in the time frame in which it is normally active. Similar deletion of Module 24 led to ubiquitous GFP expression in the gastrula and pluteus. These results show that Module 10 is uniquely necessary and sufficient to account for the early phase of gatae expression during endomesoderm specification. In addition, they imply a functional Cis-Regulatory Module exclusion, whereby only a single Module can associate with the basal promoter and drive gene expression at any given time.

  • regulation of spblimp1 krox1a an alternatively transcribed isoform expressed in midgut and hindgut of the sea urchin gastrula
    Gene Expression Patterns, 2007
    Co-Authors: Carolina B Livi, Eric H. Davidson
    Abstract:

    The sea urchin regulatory gene Spblimp1/krox produces alternatively transcribed and spliced isoforms, 1a and 1b, which have different temporal and spatial patterns of expression. Here we describe a Cis-Regulatory Module that controls the expression of the 1a splice form in the midgut and hindgut at the beginning of gastrulation. Conserved sequence patches revealed by a comparison of the blimp1/krox locus in Strongylocentrotus purpuratus and Lytechinus variegatus genomes were tested by gene transfer, in association with GFP or CAT reporter genes. An expression construct containing a conserved sequence patch immediately 5′ of exon 1a included the transcription initiation site for blimp1/krox1a. This construct displays specific mid and hindgut expression, indicating that these are the locations of endogenous blimp1/krox1a transcription during the gastrula stage. Its sequence contains binding sites for Brn1/2/4, Otx, and Blimp1/Krox itself, as predicted in a prior regulatory network analysis.

James Castelli-gair Hombría - One of the best experts on this subject based on the ideXlab platform.

  • In vivo Hox binding specificity revealed by systematic changes to a single cis regulatory Module.
    Nature communications, 2019
    Co-Authors: Carlos Sánchez-higueras, Chaitanya Rastogi, Roumen Voutev, Harmen J. Bussemaker, Richard S. Mann, James Castelli-gair Hombría
    Abstract:

    Hox proteins belong to a family of transcription factors with similar DNA binding specificities that control animal differentiation along the antero-posterior body axis. Hox proteins are expressed in partially overlapping regions where each one is responsible for the formation of particular organs and structures through the regulation of specific direct downstream targets. Thus, explaining how each Hox protein can selectively control its direct targets from those of another Hox protein is fundamental to understand animal development. Here we analyse a cis regulatory Module directly regulated by seven different Drosophila Hox proteins and uncover how different Hox class proteins differentially control its expression. We find that regulation by one or another Hox protein depends on the combination of three modes: Hox-cofactor dependent DNA-binding specificity; Hox-monomer binding sites; and interaction with positive and negative Hox-collaborator proteins. Additionally, we find that similar regulation can be achieved by Amphioxus orthologs, suggesting these three mechanisms are conserved from insects to chordates.

  • Antagonism versus cooperativity with TALE cofactors at the base of the functional diversification of Hox protein function
    PLoS Genetics, 2013
    Co-Authors: María Luisa Rivas, Jose Manuel Espinosa-vázquez, Nagraj Sambrani, Stephen Greig, Samir Merabet, Yacine Graba, James Castelli-gair Hombría
    Abstract:

    Extradenticle (Exd) and Homothorax (Hth) function as positive transcriptional cofactors of Hox proteins, helping them to bind specifically their direct targets. The posterior Hox protein Abdominal-B (Abd-B) does not require Exd/Hth to bind DNA; and, during embryogenesis, Abd-B represses hth and exd transcription. Here we show that this repression is necessary for Abd-B function, as maintained Exd/Hth expression results in transformations similar to those observed in loss-of-function Abd-B mutants. We characterize the cis regulatory Module directly regulated by Abd-B in the empty spiracles gene and show that the Exd/Hth complex interferes with Abd-B binding to this enhancer. Our results suggest that this novel Exd/Hth function does not require the complex to bind DNA and may be mediated by direct Exd/Hth binding to the Abd-B homeodomain. Thus, in some instances, the main positive cofactor complex for anterior Hox proteins can act as a negative factor for the posterior Hox protein Abd-B. This antagonistic interaction uncovers an alternative way in which MEIS and PBC cofactors can modulate Abd-B like posterior Hox genes during development.

Constance L Cepko - One of the best experts on this subject based on the ideXlab platform.

  • a gene regulatory network controls the binary fate decision of rod and bipolar cells in the vertebrate retina
    Developmental Cell, 2014
    Co-Authors: Mark M. Emerson, Constance L Cepko, Sui Wang, Cem Sengel
    Abstract:

    Gene regulatory networks (GRNs) regulate critical events during development. In complex tissues, such as the mammalian central nervous system (CNS), networks likely provide the complex regulatory interactions needed to direct the specification of the many CNS cell types. Here, we dissect a GRN that regulates a binary fate decision between two siblings in the murine retina, the rod photoreceptor and bipolar interneuron. The GRN centers on Blimp1, one of the transcription factors (TFs) that regulates the rod versus bipolar cell fate decision. We identified a Cis-Regulatory Module (CRM), B108, that mimics Blimp1 expression. Deletion of genomic B108 by CRISPR/Cas9 in vivo using electroporation abolished the function of Blimp1. Otx2 and RORβ were found to regulate Blimp1 expression via B108, and Blimp1 and Otx2 were shown to form a negative feedback loop that regulates the level of Otx2, which regulates the production of the correct ratio of rods and bipolar cells.

  • otx2 and onecut1 promote the fates of cone photoreceptors and horizontal cells and repress rod photoreceptors
    Developmental Cell, 2013
    Co-Authors: Mark M. Emerson, Natalia Surzenko, Jillian J Goetz, Jeffrey M Trimarchi, Constance L Cepko
    Abstract:

    Cone photoreceptors carry out phototransduction in daylight conditions and provide the critical first step in color vision. Despite their importance, little is known about the developmental mechanisms involved in their generation, particularly how they are determined relative to rod photoreceptors, the cells that initiate vision in dim light. Here, we report the identification of a Cis-Regulatory Module (CRM) for the thyroid hormone receptor beta (Thrb) gene, an early cone marker. We found that ThrbCRM1 is active in progenitor cells biased to the production of cones and an interneuronal cell type, the horizontal cell (HC). Molecular analysis of ThrbCRM1 revealed that it is combinatorially regulated by the Otx2 and Onecut1 transcription factors. Onecut1 is sufficient to induce cells with the earliest markers of cones and HCs. Conversely, interference with Onecut1 transcriptional activity leads to precocious rod development, suggesting that Onecut1 is critically important in defining cone versus rod fates.

Lucas Waltzer - One of the best experts on this subject based on the ideXlab platform.

  • A GATA/RUNX Cis-Regulatory Module couples Drosophila blood cell commitment and differentiation into crystal cells.
    Developmental Biology, 2007
    Co-Authors: Géraldine Ferjoux, Benoit Augé, Karène Boyer, Marc Haenlin, Lucas Waltzer
    Abstract:

    Members of the RUNX and GATA transcription factor families play critical roles during hematopoiesis from Drosophila to mammals. In Drosophila, the formation of the crystal cell hematopoietic lineage depends on the continuous expression of the lineage-specific RUNX factor Lozenge (Lz) and on its interaction with the GATA factor Serpent (Srp). Crystal cells are the main source of prophenoloxidases (proPOs), the enzymes required for melanization. By analyzing the promoter regions of several insect proPOs, we identify a conserved GATA/RUNX Cis-Regulatory Module that ensures the crystal cell-specific expression of the three Drosophila melanogaster proPO. We demonstrate that activation of this Module requires the direct binding of both Srp and Lz. Interestingly, a similar GATA/RUNX signature is over-represented in crystal cell differentiation markers, allowing us to identify new Srp/Lz target genes by genome-wide screening of Drosophila promoter regions. Finally, we show that the expression of lz in the crystal cells also relies on Srp/Lz-mediated activation via a similar Module, indicating that crystal cell fate choice maintenance and activation of the differentiation program are coupled. Based on our observations, we propose that this GATA/RUNX Cis-Regulatory Module may be reiteratively used during hematopoietic development through evolution.

  • Genomes & Developmental Control A GATA/RUNX Cis-Regulatory Module couples Drosophila blood cell commitment and differentiation into crystal cells
    2007
    Co-Authors: Géraldine Ferjoux, Benoit Augé, Karène Boyer, Marc Haenlin, Lucas Waltzer
    Abstract:

    AbstractMembers of the RUNX and GATA transcription factor families play critical roles during hematopoiesis from Drosophila to mammals. InDrosophila, the formation of the crystal cell hematopoietic lineage depends on the continuous expression of the lineage-specific RUNX factorLozenge (Lz) and on its interaction with the GATA factor Serpent (Srp). Crystal cells are the main source of prophenoloxidases (proPOs), theenzymes required for melanization. By analyzing the promoter regions of several insect proPOs, we identify a conserved GATA/RUNX Cis-Regulatory Module that ensures the crystal cell-specific expression of the three Drosophila melanogaster proPO. We demonstrate that activation ofthis Module requires the direct binding of both Srp and Lz. Interestingly, a similar GATA/RUNX signature is over-represented in crystal celldifferentiation markers, allowing us to identify new Srp/Lz target genes by genome-wide screening of Drosophila promoter regions. Finally, weshow that the expression of lz in the crystal cells also relies on Srp/Lz-mediated activation via a similar Module, indicating that crystal cell fatechoice maintenance and activation of the differentiation program are coupled. Based on our observations, we propose that this GATA/RUNX Cis-Regulatory Module may be reiteratively used during hematopoietic development through evolution.© 2007 Elsevier Inc. All rights reserved.

Po-cheng Hung - One of the best experts on this subject based on the ideXlab platform.

  • cis MEP: an integrated repository of genomic epigenetic profiles and Cis-Regulatory Modules in Drosophila
    BMC Systems Biology, 2014
    Co-Authors: Tzu-hsien Yang, Chung-ching Wang, Po-cheng Hung
    Abstract:

    Background Cis -regulatory Modules (CRMs), or the DNA sequences required for regulating gene expression, play the central role in biological researches on transcriptional regulation in metazoan species. Nowadays, the systematic understanding of CRMs still mainly resorts to computational methods due to the time-consuming and small-scale nature of experimental methods. But the accuracy and reliability of different CRM prediction tools are still unclear. Without comparative cross-analysis of the results and combinatorial consideration with extra experimental information, there is no easy way to assess the confidence of the predicted CRMs. This limits the genome-wide understanding of CRMs. Description It is known that transcription factor binding and epigenetic profiles tend to determine functions of CRMs in gene transcriptional regulation. Thus integration of the genome-wide epigenetic profiles with systematically predicted CRMs can greatly help researchers evaluate and decipher the prediction confidence and possible transcriptional regulatory functions of these potential CRMs. However, these data are still fragmentary in the literatures. Here we performed the computational genome-wide screening for potential CRMs using different prediction tools and constructed the pioneer database, cis MEP ( cis -regulatory Module epigenetic profile database), to integrate these computationally identified CRMs with genomic epigenetic profile data. cis MEP collects the literature-curated TFBS location data and nine genres of epigenetic data for assessing the confidence of these potential CRMs and deciphering the possible CRM functionality. Conclusions cis MEP aims to provide a user-friendly interface for researchers to assess the confidence of different potential CRMs and to understand the functions of CRMs through experimentally-identified epigenetic profiles. The deposited potential CRMs and experimental epigenetic profiles for confidence assessment provide experimentally testable hypotheses for the molecular mechanisms of metazoan gene regulation. We believe that the information deposited in cis MEP will greatly facilitate the comparative usage of different CRM prediction tools and will help biologists to study the modular regulatory mechanisms between different TFs and their target genes.

  • cisMEP: an integrated repository of genomic epigenetic profiles and Cis-Regulatory Modules in Drosophila.
    BMC systems biology, 2014
    Co-Authors: Tzu-hsien Yang, Chung-ching Wang, Po-cheng Hung
    Abstract:

    Cis-Regulatory Modules (CRMs), or the DNA sequences required for regulating gene expression, play the central role in biological researches on transcriptional regulation in metazoan species. Nowadays, the systematic understanding of CRMs still mainly resorts to computational methods due to the time-consuming and small-scale nature of experimental methods. But the accuracy and reliability of different CRM prediction tools are still unclear. Without comparative cross-analysis of the results and combinatorial consideration with extra experimental information, there is no easy way to assess the confidence of the predicted CRMs. This limits the genome-wide understanding of CRMs. It is known that transcription factor binding and epigenetic profiles tend to determine functions of CRMs in gene transcriptional regulation. Thus integration of the genome-wide epigenetic profiles with systematically predicted CRMs can greatly help researchers evaluate and decipher the prediction confidence and possible transcriptional regulatory functions of these potential CRMs. However, these data are still fragmentary in the literatures. Here we performed the computational genome-wide screening for potential CRMs using different prediction tools and constructed the pioneer database, cisMEP (Cis-Regulatory Module epigenetic profile database), to integrate these computationally identified CRMs with genomic epigenetic profile data. cisMEP collects the literature-curated TFBS location data and nine genres of epigenetic data for assessing the confidence of these potential CRMs and deciphering the possible CRM functionality. cisMEP aims to provide a user-friendly interface for researchers to assess the confidence of different potential CRMs and to understand the functions of CRMs through experimentally-identified epigenetic profiles. The deposited potential CRMs and experimental epigenetic profiles for confidence assessment provide experimentally testable hypotheses for the molecular mechanisms of metazoan gene regulation. We believe that the information deposited in cisMEP will greatly facilitate the comparative usage of different CRM prediction tools and will help biologists to study the modular regulatory mechanisms between different TFs and their target genes.