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Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development

Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the formation of mammalian...

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Autores principales: Aldea, Daniel, Kokalari, Blerina, Atsuta, Yuji, Dingwall, Heather L., Zheng, Ying, Nace, Arben, Cotsarelis, George, Kamberov, Yana G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934363/
https://www.ncbi.nlm.nih.gov/pubmed/36745673
http://dx.doi.org/10.1371/journal.pgen.1010614
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author Aldea, Daniel
Kokalari, Blerina
Atsuta, Yuji
Dingwall, Heather L.
Zheng, Ying
Nace, Arben
Cotsarelis, George
Kamberov, Yana G.
author_facet Aldea, Daniel
Kokalari, Blerina
Atsuta, Yuji
Dingwall, Heather L.
Zheng, Ying
Nace, Arben
Cotsarelis, George
Kamberov, Yana G.
author_sort Aldea, Daniel
collection PubMed
description Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the formation of mammalian eccrine sweat glands. We previously identified the En1 candidate enhancer (ECE) 18 cis-regulatory element that has been highly and repeatedly derived on the human lineage to potentiate ectodermal EN1 and induce our species’ uniquely high eccrine gland density. Intriguingly, ECE18 quantitative activity is negligible outside of primates and ECE18 is not required for En1 regulation and eccrine gland formation in mice, raising the possibility that distinct enhancers have evolved to modulate the same trait. Here we report the identification of the ECE20 enhancer and show it has conserved functionality in mouse and human developing skin ectoderm. Unlike ECE18, knock-out of ECE20 in mice reduces ectodermal En1 and eccrine gland number. Notably, we find ECE20, but not ECE18, is also required for En1 expression in the embryonic mouse brain, demonstrating that ECE20 is a pleiotropic En1 enhancer. Finally, that ECE18 deletion does not potentiate the eccrine phenotype of ECE20 knock-out mice supports the secondary incorporation of ECE18 into the regulation of this trait in primates. Our findings reveal that the mammalian En1 regulatory machinery diversified to incorporate both shared and lineage-restricted enhancers to regulate the same phenotype, and also have implications for understanding the forces that shape the robustness and evolvability of developmental traits.
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spelling pubmed-99343632023-02-17 Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development Aldea, Daniel Kokalari, Blerina Atsuta, Yuji Dingwall, Heather L. Zheng, Ying Nace, Arben Cotsarelis, George Kamberov, Yana G. PLoS Genet Research Article Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the formation of mammalian eccrine sweat glands. We previously identified the En1 candidate enhancer (ECE) 18 cis-regulatory element that has been highly and repeatedly derived on the human lineage to potentiate ectodermal EN1 and induce our species’ uniquely high eccrine gland density. Intriguingly, ECE18 quantitative activity is negligible outside of primates and ECE18 is not required for En1 regulation and eccrine gland formation in mice, raising the possibility that distinct enhancers have evolved to modulate the same trait. Here we report the identification of the ECE20 enhancer and show it has conserved functionality in mouse and human developing skin ectoderm. Unlike ECE18, knock-out of ECE20 in mice reduces ectodermal En1 and eccrine gland number. Notably, we find ECE20, but not ECE18, is also required for En1 expression in the embryonic mouse brain, demonstrating that ECE20 is a pleiotropic En1 enhancer. Finally, that ECE18 deletion does not potentiate the eccrine phenotype of ECE20 knock-out mice supports the secondary incorporation of ECE18 into the regulation of this trait in primates. Our findings reveal that the mammalian En1 regulatory machinery diversified to incorporate both shared and lineage-restricted enhancers to regulate the same phenotype, and also have implications for understanding the forces that shape the robustness and evolvability of developmental traits. Public Library of Science 2023-02-06 /pmc/articles/PMC9934363/ /pubmed/36745673 http://dx.doi.org/10.1371/journal.pgen.1010614 Text en © 2023 Aldea et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Aldea, Daniel
Kokalari, Blerina
Atsuta, Yuji
Dingwall, Heather L.
Zheng, Ying
Nace, Arben
Cotsarelis, George
Kamberov, Yana G.
Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development
title Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development
title_full Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development
title_fullStr Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development
title_full_unstemmed Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development
title_short Differential modularity of the mammalian Engrailed 1 enhancer network directs sweat gland development
title_sort differential modularity of the mammalian engrailed 1 enhancer network directs sweat gland development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934363/
https://www.ncbi.nlm.nih.gov/pubmed/36745673
http://dx.doi.org/10.1371/journal.pgen.1010614
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