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      ‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks

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          Abstract

          In this review, Selleri et al. illustrate how PBX proteins govern regulatory networks that direct essential morphogenetic processes and organogenesis in vertebrate development.

          Abstract

          Pbx genes encode transcription factors that belong to the TALE (three-amino-acid loop extension) superclass of homeodomain proteins. We have witnessed a surge in information about the roles of this gene family as leading actors in the transcriptional control of development. PBX proteins represent a clear example of how transcription factors can regulate developmental processes by combinatorial properties, acting within multimeric complexes to implement activation or repression of transcription depending on their interaction partners. Here, we revisit long-emphasized functions of PBX transcription factors as cofactors for HOX proteins, major architects of the body plan. We further discuss new knowledge on roles of PBX proteins in different developmental contexts as upstream regulators of Hox genes—as factors that interact with non-HOX proteins and can work independently of HOX—as well as potential pioneer factors. Committed to building a perfect body, PBX proteins govern regulatory networks that direct essential morphogenetic processes and organogenesis in vertebrate development. Perturbations of PBX-dependent networks can cause human congenital disease and cancer.

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          Transcription factors: from enhancer binding to developmental control.

          Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.
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            The Human Cell Atlas

            The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
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              A Comparative Encyclopedia of DNA Elements in the Mouse Genome

              Summary As the premier model organism in biomedical research, the laboratory mouse shares the majority of protein-coding genes with humans, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of other sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                genesdev
                genesdev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                1 March 2019
                : 33
                : 5-6
                : 258-275
                Affiliations
                [1 ]Program in Craniofacial Biology, University of California at San Francisco, San Francisco, California 94143, USA;
                [2 ]Institute of Human Genetics, University of California at San Francisco, San Francisco, California 94143, USA;
                [3 ]Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, California 94143, USA;
                [4 ]Department of Orofacial Sciences, University of California at San Francisco, San Francisco, California 94143, USA;
                [5 ]Department of Anatomy, University of California at San Francisco, San Francisco, California 94143, USA;
                [6 ]Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy;
                [7 ]The Novo Nordisk Foundation Center for Stem Cell Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark
                Author notes
                Article
                8711660
                10.1101/gad.318774.118
                6411007
                30824532
                18ee0f78-00e7-470b-821c-d0c595146a45
                © 2019 Selleri et al.; Published by Cold Spring Harbor Laboratory Press

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 18
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: RO1HD043997
                Award ID: RO1HD061403
                Award ID: RO1DE024745
                Award ID: R21DE018031
                Funded by: March of Dimes and Birth Defects Foundation
                Categories
                5
                11
                17
                Review

                pbx,tale,transcription factors,morphogenesis,organogenesis,regulatory networks

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