ArticleNature communications2024
DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Decoding the mechanisms of cooperative DNA binding by the Paired-like homeodomain family.Nature communications · 2026Article
- An inducible system to study the regulatory functions of GSX2 in human lateral ganglionic eminence-like progenitors.Developmental biology · 2026Article
- Cellular Functional Analyses ofHuman mutation · 2026Article
- Missense variants in homeobox domain of PBX1 cause coracoclavicular ankylosis.European journal of human genetics : EJHG · 2026Article
- A Structure-Guided Kinase-Transcription Factor Interactome Atlas Reveals Docking Landscapes of the Kinome.bioRxiv : the preprint server for biology · 2025Article
- Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.Cell reports · 2025Article
- Evolutionary Diversification and Adaptive Evolution Analysis of the Plant HD-Zip IV Subfamily.Genes · 2025Article
- Decoding the mechanisms of cooperative DNA binding by the Paired-like homeodomain family.bioRxiv : the preprint server for biology · 2025Article
- Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft.NPJ genomic medicine · 2025Article
- Molecular Cloning, Optimization of Expression and Functional Characterization of the Global Transcriptional Regulator MosR (Rv0348) of Mycobacterium tuberculosis.Applied biochemistry and biotechnology · 2025Article
- Predicting the DNA binding specificity of transcription factor mutants using family-level biophysically interpretable machine learning.Nucleic acids research · 2025Article
- NKX2-5 congenital heart disease mutations show diverse loss and gain of epigenomic, biochemical and chromatin search functions underpinning pathogenicity.bioRxiv : the preprint server for biology · 2025Article
- Genome-wide characterization and their roles in abiotic stress responses of HD-Zip transcription factors in pepper.BMC plant biology · 2025Article
- Missense variants in human forkhead transcription factors reveal determinants of forkhead DNA bispecificity.bioRxiv : the preprint server for biology · 2025Article
- The ALX4 dimer structure provides insight into how disease alleles impact function.Nature communications · 2025Article
- Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.Molecular cell · 2025Article
- Gene Identification for Ocular Congenital Cranial Motor Neuron Disorders Using Human Sequencing, Zebrafish Screening, and Protein Binding Microarrays.Investigative ophthalmology & visual science · 2025Article
- Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft.medRxiv : the preprint server for health sciences · 2025Article
- DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.Nature communications · 2024Article
- Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.bioRxiv : the preprint server for biology · 2024Article
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15 authors.
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Abstract
Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and are the TF structural class with the largest number of disease-associated mutations in the Human Gene Mutation Database (HGMD). Despite numerous structural studies and large-scale analyses of HD DNA binding specificity, HD-DNA recognition is still not fully understood. Here, we analyze 92 human HD mutants, including disease-associated variants and variants of uncertain significance (VUS), for their effects on DNA binding activity. Many of the variants alter DNA binding affinity and/or specificity. Detailed biochemical analysis and structural modeling identifies 14 previously unknown specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibits different effects on DNA binding activity. Variant effect prediction tools perform moderately well in distinguishing variants with altered DNA binding affinity, but poorly in identifying those with altered binding specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and the development of clinical diagnostics and precision therapies.
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