ArticleProceedings of the National Academy of Sciences of the United States of America2016
Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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110 citing papers in PubMed, 169 citations in OpenAlex.
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- Bipartite DNA binding domain of transcription factor BCL11B binds clustered short DNA sequence motifs.bioRxiv : the preprint server for biology · 2026Article
- Functional genomics analysis of developing zebrafish and human endoderm reveals highly conservedGenome research · 2026Article
- Sequence-based modeling of low-affinity transcription factor-DNA binding through deep learning.NAR genomics and bioinformatics · 2026Article
- Exploring the roles of conserved context-dependent cis-regulatory elements (cdCREs) in multicellularity, human health and disease.The FEBS journal · 2025Review
- Quantifying the impact of genetic mutations on enhancer dynamics.bioRxiv : the preprint server for biology · 2025Article
- Deep learning the dynamic regulatory sequence code of cardiac organoid differentiation.bioRxiv : the preprint server for biology · 2025Article
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- A gene regulatory network for specification and morphogenesis of a Mauthner Cell homolog in non-vertebrate chordates.Developmental biology · 2025Article
- Integrating genetic variation with deep learning provides context for variants impacting transcription factor binding during embryogenesis.Genome research · 2025Article
- Multimeric transcription factor BCL11A utilizes two zinc-finger tandem arrays to bind clustered short sequence motifs.Nature communications · 2025Article
- Interpreting regulatory mechanisms of Hippo signaling through a deep learning sequence model.Cell genomics · 2025Article
- An evolutionarily conserved constellation of functional cis-elements programs the virus-responsive fate of the human (epi)genome.Nucleic acids research · 2025Article
- Combinatorial transcription factor binding encodes cis-regulatory wiring of mouse forebrain GABAergic neurogenesis.Developmental cell · 2025Article
- Perspective on recent developments and challenges in regulatory and systems genomics.Bioinformatics advances · 2025Review
- Pax proteins mediate segment-specific functions in proximal tubule survival and response to ischemic injury.American journal of physiology. Renal physiology · 2025Article
50 more citing papers are in PubMed but not listed here.
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5 authors at 3 institutions in 1 country.
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Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.