ArticleNature communications2021
A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 citations in OpenAlex.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Promoter strength and position govern promoter competition through transcript-dependent insulation.Nature genetics · 2026Article
- A functional overlap between actively transcribed genes and chromatin insulator elements.The EMBO journal · 2026Article
- Configuring the Code: Enhancer-Promoter Arrangement and Transcriptional Regulation.Journal of molecular biology · 2026Review
- In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in β-thalassemia.Scientific reports · 2025Article
- Data-driven projections of candidate enhancer-activating SNPs in immune regulation.BMC genomics · 2025Article
- Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition.Nature communications · 2024Article
- A point mutation in thePhysiology and molecular biology of plants : an international journal of functional plant biology · 2024Article
- An efficient CRISPR-Cas12a promoter editing system for crop improvement.Nature plants · 2023Article
- Recommendations for clinical interpretation of variants found in non-coding regions of the genome.Genome medicine · 2022Article
- Enhancer-gene specificity in development and disease.Development (Cambridge, England) · 2022Review
- Erythroid Cell Research: 3D Chromatin, Transcription Factors and Beyond.International journal of molecular sciences · 2022Review
- Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development.Nature communications · 2022Article
- Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture.Nature protocols · 2022Review
- Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts.Frontiers in genetics · 2022Review
- Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.Nature genetics · 2021Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
Many single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements.
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