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The importance of being cis: evolution of orthologous fish and mammalian enhancer activity.

ABSTRACT: Conserved noncoding elements (CNEs) in vertebrate genomes often act as developmental enhancers, but a critical issue is how well orthologous CNE sequences retain the same activity in their respective species, a characteristic important for generalization of model organism studies. To quantify how well CNE enhancer activity has been preserved, we compared the anatomy-specific activities of 41 zebra fish CNEs in zebra fish embryos with the activities of orthologous human CNEs in mouse embryos. We found that 13/41 (?30%) of the orthologous CNE pairs exhibit conserved positive activity in zebra fish and mouse. Conserved positive activity is only weakly associated with either sequence conservation or the absence of bases undergoing accelerated evolution. A stronger effect is that disparate activity is associated with transcription factor binding site divergence. To distinguish the contributions of cis- versus trans-regulatory changes, we analyzed 13 CNEs in a three-way experimental comparison: human CNE tested in zebra fish, human CNE tested in mouse, and orthologous zebra fish CNE tested in zebra fish. Both cis- and trans-changes affect a significant fraction of CNEs, although human and zebra fish sequences exhibit disparate activity in zebra fish (indicating cis regulatory changes) twice as often as human sequences show disparate activity when tested in mouse and zebra fish (indicating trans regulatory changes). In all four cases where the zebra fish and human CNE display a similar expression pattern in zebra fish, the human CNE also displays a similar expression pattern in mouse. This suggests that the endogenous enhancer activity of ?30% of human CNEs can be determined from experiments in zebra fish alone, and to identify these CNEs, both the zebra fish and the human sequences should be tested.

SUBMITTER: Ritter DI

PROVIDER: S-EPMC3107594 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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The importance of being cis: evolution of orthologous fish and mammalian enhancer activity.

Ritter Deborah I DI Li Qiang Q Kostka Dennis D Pollard Katherine S KS Guo Su S Chuang Jeffrey H JH

Molecular biology and evolution 20100521 10

Conserved noncoding elements (CNEs) in vertebrate genomes often act as developmental enhancers, but a critical issue is how well orthologous CNE sequences retain the same activity in their respective species, a characteristic important for generalization of model organism studies. To quantify how well CNE enhancer activity has been preserved, we compared the anatomy-specific activities of 41 zebra fish CNEs in zebra fish embryos with the activities of orthologous human CNEs in mouse embryos. We ...[more]

PMID: 20494938

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Project description:BackgroundModels that incorporate specific chemical mechanisms have been successful in describing the activity of Drosophila developmental enhancers as a function of underlying transcription factor binding motifs. Despite this, the minimum set of mechanisms required to reconstruct an enhancer from its constituent parts is not known. Synthetic biology offers the potential to test the sufficiency of known mechanisms to describe the activity of enhancers, as well as to uncover constraints on the number, order, and spacing of motifs.ResultsUsing a functional model and in silico compensatory evolution, we generated putative synthetic even-skipped stripe 2 enhancers with varying degrees of similarity to the natural enhancer. These elements represent the evolutionary trajectories of the natural stripe 2 enhancer towards two synthetic enhancers designed ab initio. In the first trajectory, spatially regulated expression was maintained, even after more than a third of binding sites were lost. In the second, sequences with high similarity to the natural element did not drive expression, but a highly diverged sequence about half the length of the minimal stripe 2 enhancer drove ten times greater expression. Additionally, homotypic clusters of Zelda or Stat92E motifs, but not Bicoid, drove expression in developing embryos.ConclusionsHere, we present a functional model of gene regulation to test the degree to which the known transcription factors and their interactions explain the activity of the Drosophila even-skipped stripe 2 enhancer. Initial success in the first trajectory showed that the gene regulation model explains much of the function of the stripe 2 enhancer. Cases where expression deviated from prediction indicates that undescribed factors likely act to modulate expression. We also showed that activation driven Bicoid and Hunchback is highly sensitive to spatial organization of binding motifs. In contrast, Zelda and Stat92E drive expression from simple homotypic clusters, suggesting that activation driven by these factors is less constrained. Collectively, the 40 sequences generated in this work provides a powerful training set for building future models of gene regulation.

Dataset Information

The importance of being cis: evolution of orthologous fish and mammalian enhancer activity.

Publications

The importance of being cis: evolution of orthologous fish and mammalian enhancer activity.

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