ArticleDevelopmental cell2023
Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development.
Article in Developmental cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Decoding RNA-protein interactions using high-throughput methods.RNA biology · 2026Review
- Mechanisms and functional implications of long-range enhancer-dependent gene regulation.Nature genetics · 2026Review
- Amplification of MED30 at chromosome 8q24 reprograms MYC binding to low-affinity oncogenic enhancers in cancer cells.Cell reports · 2026Article
- Retracing and rewriting the evolutionary trajectories of mammalian developmental enhancers.bioRxiv : the preprint server for biology · 2026Article
- Multi-scale dissection, compaction and derivatization of mammalian developmental enhancers.bioRxiv : the preprint server for biology · 2026Article
- Non-coding RNAs in congenital heart disease and placental development: Bridging molecular mechanisms to clinical biomarkers and therapies.Non-coding RNA research · 2026Review
- Quantitative modulation of a spatial enhancer through the biophysical properties of a transcription factor binding site.Science advances · 2026Article
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Role of eRNAs in Cardiovascular Diseases.Current cardiology reviews · 2026Review
- Functional architecture of cardiac TF regulatory landscapes in control of mammalian heart development.bioRxiv : the preprint server for biology · 2025Article
- Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.Cell reports · 2025Article
- Deep learning the dynamic regulatory sequence code of cardiac organoid differentiation.bioRxiv : the preprint server for biology · 2025Article
- Programming human cell type-specific gene expression via an atlas of AI-designed enhancers.bioRxiv : the preprint server for biology · 2025Article
- Article
- Cardiac enhancers: Gateway to the regulatory mechanisms of heart regeneration.Seminars in cell & developmental biology · 2025Review
- Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.bioRxiv : the preprint server for biology · 2025Article
- Dissecting cardiovascular disease-associated noncoding genetic variants using human iPSC models.Stem cell reports · 2025Review
- Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage.Cell genomics · 2025Article
- Positive autoregulation of Sox17 is necessary for gallbladder and extrahepatic bile duct formation.Development (Cambridge, England) · 2025Article
- Mutations to transcription factor MAX allosterically increase DNA selectivity by altering folding and binding pathways.Nature communications · 2025Article
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Authors and funding
13 authors.
Funding
Abstract
Transcriptional enhancers direct precise gene expression patterns during development and harbor the majority of variants associated with phenotypic diversity, evolutionary adaptations, and disease. Pinpointing which enhancer variants contribute to changes in gene expression and phenotypes is a major challenge. Here, we find that suboptimal or low-affinity binding sites are necessary for precise gene expression during heart development. Single-nucleotide variants (SNVs) can optimize the affinity of ETS binding sites, causing gain-of-function (GOF) gene expression, cell migration defects, and phenotypes as severe as extra beating hearts in the marine chordate Ciona robusta. In human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a SNV within a human GATA4 enhancer increases ETS binding affinity and causes GOF enhancer activity. The prevalence of suboptimal-affinity sites within enhancers creates a vulnerability whereby affinity-optimizing SNVs can lead to GOF gene expression, changes in cellular identity, and organismal-level phenotypes that could contribute to the evolution of novel traits or diseases.
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