Conservation of transcription factor binding specificities across 600 million years of bilateria evolution

Nitta, Kazuhiro R.; Jolma, Arttu; Yin, Yimeng; Morgunova, Ekaterina; Kivioja, Teemu; Akhtar, Junaid; Hens, Korneel; Toivonen, Jarkko; Deplancke, Bart; Furlong, Eileen E. M.; Taipale, Jussi

doi:10.7554/elife.04837

Cited by 337 publications

(264 citation statements)

References 74 publications

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“…It is possible to determine relative binding affinities of the native sites by analyzing the frequency of selected sequences, using high-throughput binding datasets (27)(28)(29). Relative affinities were calculated using median signal intensities of the universal protein binding microarray data for mouse ETS-1 (17) proteins from the UniProbe database (thebrain.…”

Section: Methodsmentioning

confidence: 99%

Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers

Farley

Olson

Zhang

et al. 2016

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

146

159

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Transcriptional enhancers are short segments of DNA that switch genes on and off in response to a variety of intrinsic and extrinsic signals. Despite the discovery of the first enhancer more than 30 y ago, the relationship between primary DNA sequence and enhancer activity remains obscure. In particular, the importance of "syntax" (the order, orientation, and spacing of binding sites) is unclear. A high-throughput screen identified synthetic notochord enhancers that are activated by the combination of ZicL and ETS transcription factors in Ciona embryos. Manipulation of these enhancers elucidated a "regulatory code" of sequence and syntax features for notochord-specific expression. This code enabled in silico discovery of bona fide notochord enhancers, including those containing low-affinity binding sites that would be excluded by standard motif identification methods. One of the newly identified enhancers maps upstream of the known enhancer that regulates Brachyury (Ci-Bra), a key determinant of notochord specification. This newly identified Ci-Bra shadow enhancer contains binding sites with very low affinity, but optimal syntax, and therefore mediates surprisingly strong expression in the notochord. Weak binding sites are compensated by optimal syntax, whereas enhancers containing high-affinity binding affinities possess suboptimal syntax. We suggest this balance has obscured the importance of regulatory syntax, as noncanonical binding motifs are typically disregarded by enhancer detection methods. As a result, enhancers with low binding affinities but optimal syntax may be a vastly underappreciated feature of the regulatory genome.enhancer | gene regulation | transcription | enhancer grammar | regulatory principles P revious studies have highlighted the importance of sequence constraints within developmental enhancers for tissue-specific patterns of gene expression in both Drosophila and Ciona embryos (1-6). For example, the 69-bp orthodenticle homeobox (Otx)-a enhancer mediates restricted expression in the Ciona neural plate in response to pleiotropic fibroblast growth factor (FGF) signaling (7-9). Specificity depends on a series of low-affinity binding sites for the transcription factors ETS (FGF signaling) and GATA (ectoderm determinant) (2). Modification of these sites to improve their binding affinities resulted in augmented levels of gene expression in the neural plate, as well as ectopic expression in additional tissues that respond to FGF signaling (2).These observations prompted the suggestion that the evolution of developmental enhancers depends on the selection of submaximal binding sites. This "suboptimization" might also apply to the organization of enhancers, as changing the spacing of neighboring GATA and ETS binding sites resulted in a significant increase in enhancer activity (2). Modified Otx-a enhancers containing both optimal binding sites and optimal spacing of neighboring sites mediated intense expression in a variety of tissues responding to FGF, including the neural plate, notochord, an...

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Section: Methodsmentioning

confidence: 99%

Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers

Farley

Olson

Zhang

et al. 2016

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

146

159

View full text Add to dashboard Cite

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“…The HT-SELEX analysis for the ZNF394 was performed as in ) and the generated sequencing data was analyzed as in (Nitta et al 2015).…”

Section: Ht-selexmentioning

confidence: 99%

Multiparameter functional diversity of human C2H2 zinc finger proteins

et al. 2016

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C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2-ZF arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. In addition, little is known about whether or how these proteins regulate transcription. Most of the ∼700 human C2H2-ZF proteins also contain at least one KRAB, SCAN, BTB, or SET domain, suggesting that they may have common interacting partners and/or effector functions. Here, we report a multifaceted functional analysis of 131 human C2H2-ZF proteins, encompassing DNA binding sites, interacting proteins, and transcriptional response to genetic perturbation. We confirm the expected diversity in DNA binding motifs and genomic binding sites, and provide motif models for 78 previously uncharacterized C2H2-ZF proteins, most of which are unique. Surprisingly, the diversity in protein–protein interactions is nearly as high as diversity in DNA binding motifs: Most C2H2-ZF proteins interact with a unique spectrum of co-activators and co-repressors. Thus, multiparameter diversification likely underlies the evolutionary success of this large class of human proteins.

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“…The SoxN motif was downloaded from the TRANSFAC database, generated from HT-SELEX data (Nitta et al, 2015). Matches were filtered out with a threshold of P<0.001.…”

Section: Binding Site Predictionmentioning

confidence: 99%

SoxNeuro and shavenbaby act cooperatively to shape denticles in the embryonic epidermis of Drosophila

Rizzo

Bejsovec

2017

Development

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During development, extracellular signals are integrated by cells to induce the transcriptional circuitry that controls morphogenesis. In the fly epidermis, Wingless (Wg)/Wnt signaling directs cells to produce either a distinctly shaped denticle or no denticle, resulting in a segmental pattern of denticle belts separated by smooth, or 'naked', cuticle. Naked cuticle results from Wg repression of shavenbaby (svb), which encodes a transcription factor required for denticle construction. We have discovered that although the svb promoter responds differentially to altered Wg levels, Svb alone cannot produce the morphological diversity of denticles found in wild-type belts. Instead, a second Wg-responsive transcription factor, SoxNeuro (SoxN), cooperates with Svb to shape the denticles. Coexpressing ectopic SoxN with svb rescued diverse denticle morphologies. Conversely, removing SoxN activity eliminated the residual denticles found in svb mutant embryos. Furthermore, several known Svb target genes are also activated by SoxN, and we have discovered two novel target genes of SoxN that are expressed in denticle-producing cells and that are regulated independently of Svb. We conclude that proper denticle morphogenesis requires transcriptional regulation by both SoxN and Svb.

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Conservation of transcription factor binding specificities across 600 million years of bilateria evolution

Cited by 337 publications

References 74 publications

Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers

Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers

Multiparameter functional diversity of human C2H2 zinc finger proteins

SoxNeuro and shavenbaby act cooperatively to shape denticles in the embryonic epidermis of Drosophila

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