Regulation in common: Sponge to zebrafish

doi:10.1126/science.abe9317

GSTDTAP > 气候变化

DOI	10.1126/science.abe9317
	Regulation in common: Sponge to zebrafish
	Nathan Harmston
	2020-11-06
发表期刊	Science
出版年	2020
英文摘要	During the development of multicellular animals, distal gene regulatory sequences called enhancers are involved in determining when, where, and how much a gene is expressed ([ 1 ][1]). Enhancers contain transcription factor binding sites (TFBSs), and the combination of TFs bound determines the activity of an enhancer. There is a lack of understanding about how an enhancer sequence interprets regulatory state (input) to drive target gene expression (output), and how these sequences are constrained and/or modified over time. On page 681 of this issue, Wong et al. ([ 2 ][2]) identify a series of enhancers in a marine sponge ( Amphimedon queenslandica ) that respond to TFs expressed during zebrafish ( Danio rerio ) development. Given the large evolutionary distance between zebrafish and sponge (their common ancestor existed more than 700 million years ago), these enhancers lack detectable sequence homology with vertebrate genomes, yet their ability to function as enhancers in zebrafish demonstrates some kind of functional conservation without sequence conservation. Throughout Metazoa, numerous pairs of genes have been identified that are conserved together, a phenomenon known as microsynteny, thought to arise primarily from cis-regulatory constraints ([ 3 ][3], [ 4 ][4]). By investigating gene pairs conserved across Metazoa, Wong et al. identified and tested a set of enhancers present within the intron of one member of a pair (the bystander gene), whose function is to regulate the expression of the other gene (the target gene) in the pair. Insertion of the sponge Islet-Scaper gene pair into zebrafish embryos revealed that eISL , an enhancer located in the intron of Scaper , drove the expression of Islet in neuronal cells, similar to the expression patterns of the zebrafish paralogs of Islet . Intriguingly, eISL could drive Islet expression in neurons, a cell type not present in sponges (see the figure). Therefore, this enhancer is responding to the set of TFs expressed in zebrafish neurons and driving expression of Islet . These findings are important for understanding both how enhancers are structured and evolve, and how gene regulatory networks are reused and co-opted. A large number of enhancers appear to be species-specific ([ 5 ][5]); however, there are a subset of enhancers that are conserved between evolutionary distant species. Comparing the genomes of different species within the same phyla has identified elements that show high noncoding conservation and which act as enhancers to regulate the expression of key developmental transcription factors ([ 3 ][3]). Mutations affecting these elements have been found to have substantial effects on phenotypes and in many cases are associated with developmental disorders ([ 6 ][6]). Therefore, small changes in enhancer sequence can have large effects on function and phenotype. ![Figure][7] Conserved enhancers Injection of the entire Scaper-Islet locus of a marine sponge ( Amphimedon queenslandica ) into zebrafish ( Danio rerio ) embryos reveals that eISL (dark blue circle), a developmental enhancer located within an intron of Scaper , can drive Islet expression in zebrafish neurons. The eISL -driven gene expression patterns overlap with that of zebrafish orthologs of Islet. GRAPHIC: A. KITTERMAN/ SCIENCE However, between closely related Drosophila (fruitfly) species, the content, ordering, and positioning of TFBSs (its cis-regulatory grammar) within the eve stripe 2 enhancer are different, yet all of the configurations lead to the same phenotype, indicating functional conservation despite a lack of sequence conservation ([ 7 ][8]). A brain enhancer that is functionally conserved between chordates and hemichordates has been identified. This enhancer can regulate the expression of sonic hedgehog ( Shh ) or hedgehog ( hh ) genes during brain development in mouse and acorn worm, respectively. Despite being distinct at the level of their overall DNA sequence, these brain enhancers are comparable in terms of their constituent TFBSs ([ 8 ][9]). Together, these examples highlight that selection pressure on the output of some enhancers drives the conservation of enhancer sequence, whereas for other enhancers, sequence conservation does not appear to matter, and despite major differences in their organization, such enhancers are capable of generating the same output. Intriguingly, the set of enhancers identified by Wong et al. , though not conserved at the sequence level, can drive expression of their corresponding target gene in patterns similar to those of their orthologs, but do not regulate expression in comparable cell types. Multiple models have been proposed for how enhancers are structured in terms of the ordering and positioning of their TFBSs and the effect this has on the co-operative or additive binding of TFs to them. These range from the enhanceosome model, which requires the precise positioning of TFBSs ([ 9 ][10]), to the billboard model, where the order and positioning of TFBSs are not important ([ 10 ][11]), with the TF collective model allowing for cooperativity between TFs despite the lack of a well-defined grammar ([ 11 ][12]). Each of these models of enhancer organization implies distinct constraints on how enhancers evolve. Wong et al. used the set of TFBSs identified in eISL to search for similar sequences in other genomes and identified sequences in human, mouse, zebrafish, and fruitfly that had a similar TFBS content and were active in neuronal cell types. Although there was no apparent conservation between the entire sequences of eISL and these enhancers, short, conserved blocks of TFBSs were identified between them, indicative of a TF collective–like model for this enhancer. This indicates the existence of a common cis-regulatory grammar that is used across multiple lineages to regulate developmental gene expression in specific cell types, and furthermore suggests the presence of a regulatory state that has been reused or co-opted throughout evolution. Together, these results indicate that there is a complex relationship between the structure and function of an enhancer and the gene regulatory networks that it is a part of, with each imposing constraints on the other ([ 12 ][13], [ 13 ][14]). The mismatch between their sequence and functional conservation raises questions about how to define when two enhancers are identical. In cases where there is a clear evolutionary history and similar function, it seems obvious that these enhancers are the same. But what if parts or the whole of an enhancer have turned over, resulting in a lack of observable sequence homology but still having the same function–is this still the same enhancer? Moreover, what techniques can be used to identify and characterize them? The eISL enhancer is not a true functional equivalent of the zebrafish enhancer, yet it is capable of driving overlapping patterns of gene expression. A critical question in understanding enhancer evolution is what causes some enhancers to require high sequence conservation to ensure conserved activity, whereas for others this does not matter ([ 14 ][15])? Only through a combination of experimental and computational techniques is it possible to begin to systematically dissect the complex interplay of features affecting enhancer evolution to begin to fully understand the cis-regulatory grammar ([ 15 ][16]). 1. [↵][17]1. I. Miguel-Escalada et al ., Curr. Opin. Genet. Dev. 33, 71 (2015). [OpenUrl][18] 2. [↵][19]1. E. Wong et al ., Science 370, eaax8137 (2020). [OpenUrl][20][Abstract/FREE Full Text][21] 3. [↵][22]1. P. G. Engström et al ., Genome Res. 17, 1898 (2007). [OpenUrl][23][Abstract/FREE Full Text][24] 4. 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[OpenUrl][59][Abstract/FREE Full Text][60] 13. [↵][61]1. P. Khoueiry et al ., eLife 6, e28440 (2017). [OpenUrl][62] 14. [↵][63]1. N. Harmston et al ., Philos. Trans. Royal Soc. B Biol. Sci. 368, 20130021 (2013). [OpenUrl][64][CrossRef][65][PubMed][66] 15. [↵][67]1. T. Fuqua et al ., Nature 10.1038/s41586-020-2816-5 (2020). Acknowledgments: Thanks to E. Chua for her constructive comments. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/301987
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Nathan Harmston. Regulation in common: Sponge to zebrafish[J]. Science,2020.
APA	Nathan Harmston.(2020).Regulation in common: Sponge to zebrafish.Science.
MLA	Nathan Harmston."Regulation in common: Sponge to zebrafish".Science (2020).