| Autor: |
Aldea, Daniel, Kokalari, Blerina, Atsuta, Yuji, Dingwall, Heather L., Zheng, Ying, Nace, Arben, Cotsarelis, George, Kamberov, Yana G. |
| Předmět: |
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| Zdroj: |
PLoS Genetics; 2/6/2023, Vol. 18 Issue 2, p1-20, 20p |
| Abstrakt: |
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. Author summary: Enhancers are regulatory elements in the genome that modulate the expression of protein-coding genes by directing how much, where, or when a given gene is expressed. Accordingly, enhancers are major determinants of mammalian traits and thought to be the predominant drivers of evolutionary change. Here we interrogated the identity and compared the functionality of the enhancers that control the specification of a single, highly variable trait, the density of sweat glands in mammalian skin, by regulating expression of the mammalian Engrailed 1 (En1) gene during development. We find that mammals have evolved two distinct types of enhancers to regulate this single trait: a shared enhancer active in multiple mammalian species that not only controls En1 expression in the skin but also in the brain, and also an enhancer whose activity is restricted to the skin of primates and rapidly evolved on this lineage to affect sweat phenotypes. Our findings implicate differences in the intrinsic properties of enhancers, namely the extent to which their activity is restricted to a specific context, in shaping not only the complexity of the regulatory landscape of a developmental gene but also the means by which that landscape evolves to generate trait variation. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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