ArticleGenome research2018
A massively parallel reporter assay reveals context-dependent activity of homeodomain binding sites in vivo.
Article in Genome research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 59 citations in OpenAlex.
- Gene regulatory behaviors of mutant CRX proteins demonstrated with late-stage human retinal organoids.Human molecular genetics · 2026Article
- Decoding the mechanisms of cooperative DNA binding by the Paired-like homeodomain family.Nature communications · 2026Article
- Single-cell atlas of the transcriptome and chromatin accessibility in the human retina.Nature genetics · 2026Article
- Conservation of cis-regulatory codes over half a billion years of evolution.Science advances · 2025Article
- Decoding the mechanisms of cooperative DNA binding by the Paired-like homeodomain family.bioRxiv : the preprint server for biology · 2025Article
- The ALX4 dimer structure provides insight into how disease alleles impact function.Nature communications · 2025Article
- Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominantGenome research · 2025Article
- Active learning of enhancers and silencers in the developing neural retina.Cell systems · 2025Article
- Pathogenic variants inGenome research · 2024Article
- Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominantbioRxiv : the preprint server for biology · 2024Article
- Transcription factor interactions explain the context-dependent activity of CRX binding sites.PLoS computational biology · 2024Article
- Transcriptional precision in photoreceptor development and diseases - Lessons from 25 years of CRX research.Frontiers in cellular neuroscience · 2024Review
- CRX haploinsufficiency compromises photoreceptor precursor translocation and differentiation in human retinal organoids.Stem cell research & therapy · 2023Article
- Pathogenic variants in Crx have distinct cis-regulatory effects on enhancers and silencers in photoreceptors.bioRxiv : the preprint server for biology · 2023Article
- Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms.eLife · 2023Article
- Active learning of enhancer and silencer regulatory grammar in photoreceptors.bioRxiv : the preprint server for biology · 2023Article
- Prediction of cooperative homeodomain DNA binding sites from high-throughput-SELEX data.Nucleic acids research · 2023Article
- Massively Parallel Reporter Assays for High-Throughput In Vivo Analysis of Cis-Regulatory Elements.Journal of cardiovascular development and disease · 2023Review
- A single-cell massively parallel reporter assay detects cell-type-specific gene regulation.Nature genetics · 2023Article
- Functional analysis of the Vsx2 super-enhancer uncovers distinct cis-regulatory circuits controlling Vsx2 expression during retinogenesis.Development (Cambridge, England) · 2022Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cone-rod homeobox (CRX) is a paired-like homeodomain transcription factor (TF) and a master regulator of photoreceptor development in vertebrates. The in vitro DNA binding preferences of CRX have been described in detail, but the degree to which in vitro binding affinity is correlated with in vivo enhancer activity is not known. In addition, paired-class homeodomain TFs can bind DNA cooperatively as both homodimers and heterodimers at inverted TAAT half-sites separated by 2 or 3 nucleotides. This dimeric configuration is thought to mediate target specificity, but whether monomeric and dimeric sites encode distinct levels of activity is not known. Here, we used a massively parallel reporter assay to determine how local sequence context shapes the regulatory activity of CRX binding sites in mouse photoreceptors. We assayed inactivating mutations in more than 1700 TF binding sites and found that dimeric CRX binding sites act as stronger enhancers than monomeric CRX binding sites. Furthermore, the activity of dimeric half-sites is cooperative, dependent on a strict 3-bp spacing, and tuned by the identity of the spacer nucleotides. Saturating single-nucleotide mutagenesis of 195 CRX binding sites showed that, on average, changes in TF binding site affinity are correlated with changes in regulatory activity, but this relationship is obscured when considering mutations across multiple
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Registered trials
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.