Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity
| Autor: | Robert Reinhardt, Jonas Malkmus, Javier Lopez-Rios, Bonnie K. Kircher, Koh Onimaru, Amandine Duchesne, Rushikesh Sheth, Francisca Leal, Shalu Jhanwar, Aimée Zuniga, Laurène Ramos Martins, Kevin A. Peterson, Rolf Zeller, Victorio Palacio, Martin J. Cohn |
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| Přispěvatelé: | University of Basel (Unibas), University of Florida [Gainesville] (UF), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidad Pablo de Olavide [Sevilla] (UPO), The Jackson Laboratory [Bar Harbor] (JAX), RIKEN Center for Biosystems Dynamics Research [Kobe] (RIKEN BDR), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Spanish Government BFU2017-82974-PEuropean CommissionMDM-2016-0687Special Postdoctoral Researcher Program of RIKEN, European Project: 695032,INTEGRAL, European Commission, University of Basel, National Institutes of Health (US), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2021 |
| Předmět: |
Embryo
Nonmammalian Swine [SDV]Life Sciences [q-bio] General Physics and Astronomy Mesoderm Mice 0302 clinical medicine Gene expression Protein Isoforms Phylogeny 0303 health sciences Multidisciplinary Gene Expression Regulation Developmental Biological Evolution Cell biology Enhancer Elements Genetic medicine.anatomical_structure Signalling embryonic structures Animal Fins Intercellular Signaling Peptides and Proteins Rabbits Evolutionary developmental biology Signal Transduction animal structures Limb Buds Science Mice Transgenic Biology Article Evolutionary genetics General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Limb bud Sequence Homology Nucleic Acid medicine Animals Enhancer 030304 developmental biology Base Sequence Human evolutionary genetics Robustness (evolution) General Chemistry Embryo Mammalian Reverse Genetics Boidae Iguanas Sharks Cattle Chickens Sequence Alignment 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) Nature Communications, 2021, 12 (1), pp.5557. ⟨10.1038/s41467-021-25810-1⟩ Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-25810-1 |
| Popis: | Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs. This research was initiated with support from the Bonus-of-Excellence SNF grant 310030B_166685 (to A.Z. and R.Z.) and then supported by the ERC advanced grant INTEGRAL ERC-2015-AdG; Project ID 695032 (to R.Z.) and the University of Basel provided core funding (to A.Z. and R.Z.). Additional funding support was provided by the National Institutes of Health grant R01 GM124251 (to K.A.P.). The research of J.L.R. is supported by MICINN grants BFU2017-82974-P and MDM-2016-0687. K.O. is supported by the Special Postdoctoral Researcher Program of RIKEN. |
| Databáze: | OpenAIRE |
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