Functional regulatory evolution outside of the minimal <i>even-skipped</i> stripe 2 enhancer

Crocker, Justin; Stern, David L.

doi:10.1242/dev.149427

Cited by 16 publications

(15 citation statements)

References 61 publications

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“…Therefore, to understand how a spatial pattern of gene expression is encoded in the sequence of an enhancer, it is necessary to measure quantitative variation of gene expression in space in the tissue where the enhancer is active. Leading this endeavor, recent studies have quantified spatial enhancer activity but without considering the pattern itself as a quantitative object (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Regulatory encoding of quantitative variation in spatial activity of a Drosophila enhancer

et al. 2020

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Developmental enhancers control the expression of genes prefiguring morphological patterns. The activity of an enhancer varies among cells of a tissue, but collectively, expression levels in individual cells constitute a spatial pattern of gene expression. How the spatial and quantitative regulatory information is encoded in an enhancer sequence is elusive. To link spatial pattern and activity levels of an enhancer, we used systematic mutations of the yellow spot enhancer, active in developing Drosophila wings, and tested their effect in a reporter assay. Moreover, we developed an analytic framework based on the comprehensive quantification of spatial reporter activity. We show that the quantitative enhancer activity results from densely packed regulatory information along the sequence, and that a complex interplay between activators and multiple tiers of repressors carves the spatial pattern. Our results shed light on how an enhancer reads and integrates trans-regulatory landscape information to encode a spatial quantitative pattern.

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Section: Introductionmentioning

confidence: 99%

Regulatory encoding of quantitative variation in spatial activity of a Drosophila enhancer

et al. 2020

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“…Moreover, fragments are often chosen either arbitrarily or based on sequence conservation or genomic marks to limit the risk of disrupting functional features. These fragments can pinpoint minimal enhancers but fail to determine whether the same sequences at their locus of origin are necessary and sufficient to recapitulate the transcriptional activity of their cognate target gene ( 13 – 15 ). Finally, the representation of enhancers as rectangular boxes or stretches of sequence eludes the actual distribution of regulatory information along the enhancer sequence with different segments contributing different inputs (activation, repression, permissivity) and different activity levels.…”

mentioning

confidence: 99%

Ancestral and derived transcriptional enhancers share regulatory sequence and a pleiotropic site affecting chromatin accessibility

Xin

Poul

Ling

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The diversity of forms in multicellular organisms originates largely from the spatial redeployment of developmental genes [S. B. Carroll, Cell 134, 25–36 (2008)]. Several scenarios can explain the emergence of cis-regulatory elements that govern novel aspects of a gene expression pattern [M. Rebeiz, M. Tsiantis, Curr. Opin. Genet. Dev. 45, 115–123 (2017)]. One scenario, enhancer co-option, holds that a DNA sequence producing an ancestral regulatory activity also becomes the template for a new regulatory activity, sharing regulatory information. While enhancer co-option might fuel morphological diversification, it has rarely been documented [W. J. Glassford et al., Dev. Cell 34, 520–531 (2015)]. Moreover, if two regulatory activities are borne from the same sequence, their modularity, considered a defining feature of enhancers [J. Banerji, L. Olson, W. Schaffner, Cell 33, 729–740 (1983)], might be affected by pleiotropy. Sequence overlap may thereby play a determinant role in enhancer function and evolution. Here, we investigated this problem with two regulatory activities of the Drosophila gene yellow, the novel spot enhancer and the ancestral wing blade enhancer. We used precise and comprehensive quantification of each activity in Drosophila wings to systematically map their sequences along the locus. We show that the spot enhancer has co-opted the sequences of the wing blade enhancer. We also identified a pleiotropic site necessary for DNA accessibility of a shared regulatory region. While the evolutionary steps leading to the derived activity are still unknown, such pleiotropy suggests that enhancer accessibility could be one of the molecular mechanisms seeding evolutionary co-option.

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“…Moreover, MSE2 provides a lower rate of rescue of lethality than does the full S2E [69]. S2E, in turn, was first identified by the presence of two conserved sequences at either end [70], but this structural feature says nothing about the actual functional limits of S2E, which are known to be larger in the closely related species D. erecta [71]. Moreover there is evidence from the sea squirt Ciona that redundancy built into enhancers ensures robust expression in appropriate tissues without disrupting specificity [72].…”

Section: Discussionmentioning

confidence: 99%

An in silico analysis of robust but fragile gene regulation links enhancer length to robustness

2019

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Organisms must ensure that expression of genes is directed to the appropriate tissues at the correct times, while simultaneously ensuring that these gene regulatory systems are robust to perturbation. This idea is captured by a mathematical concept called r-robustness, which says that a system is robust to a perturbation in up to r − 1 randomly chosen parameters. r-robustness implies that the biological system has a small number of sensitive parameters and that this number can be used as a robustness measure. In this work we use this idea to investigate the robustness of gene regulation using a sequence level model of the Drosophila melanogaster gene even-skipped. We consider robustness with respect to mutations of the enhancer sequence and with respect to changes of the transcription factor concentrations. We find that gene regulation is r-robust with respect to mutations in the enhancer sequence and identify a number of sensitive nucleotides. In both natural and in silico predicted enhancers, the number of nucleotides that are sensitive to mutation correlates negatively with the length of the sequence, meaning that longer sequences are more robust. The exact degree of robustness obtained is dependent not only on DNA sequence, but also on the local concentration of regulatory factors. We find that gene regulation can be remarkably sensitive to changes in transcription factor concentrations at the boundaries of expression features, while it is robust to perturbation elsewhere.

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Functional regulatory evolution outside of the minimal even-skipped stripe 2 enhancer

Cited by 16 publications

References 61 publications

Regulatory encoding of quantitative variation in spatial activity of a Drosophila enhancer

Regulatory encoding of quantitative variation in spatial activity of a Drosophila enhancer

Ancestral and derived transcriptional enhancers share regulatory sequence and a pleiotropic site affecting chromatin accessibility

An in silico analysis of robust but fragile gene regulation links enhancer length to robustness

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