ArticlePLoS biology2020
Discovery of genes required for body axis and limb formation by global identification of retinoic acid-regulated epigenetic marks.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- Epigenetic regulation of vertebrate limb development: from field specification to tissue morphogenesis.Epigenetics · 2026Review
- Depolymerizing F-actin accelerates the exit from pluripotency to enhance stem cell-derived islet differentiation.Nature communications · 2026Article
- Cranial neural crest shortage leads to extensive craniofacial anomalies in mice mutant for the NR2F1/2 nuclear receptors.Developmental biology · 2026Article
- Molecular analysis of Aldh1a2 conditional inactivation in developing limbs reveals mechanisms of retinoic-acid mediated interdigital apoptosis.Frontiers in cell and developmental biology · 2026Article
- A dual enhancer-attenuator element ensures transient Cdx2 expression during mouse posterior body formation.Developmental cell · 2025Article
- Article
- Zebrafish sall1a and sall4 contribute to body elongation.Developmental biology · 2025Article
- Early retinoic acid signaling organizes the body axis and defines domains for the forelimb and eye.Current topics in developmental biology · 2025Review
- miR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region.International journal of molecular sciences · 2024Article
- Alteration of Gene Expression in Pathological Keratinization of the Ocular Surface.Investigative ophthalmology & visual science · 2024Article
- Rewiring of the epigenome and chromatin architecture by exogenously induced retinoic acid signaling during zebrafish embryonic development.Nucleic acids research · 2024Article
- Generation and molecular characterization of human pluripotent stem cell-derived pharyngeal foregut endoderm.Developmental cell · 2023Article
- Article
- Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.Nature genetics · 2023Article
- Understanding and modeling regional specification of the human ganglionic eminence.Stem cell reports · 2023Article
- Genetic loss-of-function does not support gain-of-function studies suggesting retinoic acid controls limb bud timing and scaling.Frontiers in cell and developmental biology · 2023Article
- Retinoic acid, RARs and early development.Journal of molecular endocrinology · 2022Article
- Pharmacological retinoic acid alters limb patterning during regeneration but endogenous retinoic acid is not required.Regenerative medicine · 2022Article
- Retinoids in the Pathogenesis and Treatment of Liver Diseases.Nutrients · 2022Review
- Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Identification of target genes that mediate required functions downstream of transcription factors is hampered by the large number of genes whose expression changes when the factor is removed from a specific tissue and the numerous binding sites for the factor in the genome. Retinoic acid (RA) regulates transcription via RA receptors bound to RA response elements (RAREs) of which there are thousands in vertebrate genomes. Here, we combined chromatin immunoprecipitation sequencing (ChIP-seq) for epigenetic marks and RNA-seq on trunk tissue from wild-type and Aldh1a2-/- embryos lacking RA synthesis that exhibit body axis and forelimb defects. We identified a relatively small number of genes with altered expression when RA is missing that also have nearby RA-regulated deposition of histone H3 K27 acetylation (H3K27ac) (gene activation mark) or histone H3 K27 trimethylation (H3K27me3) (gene repression mark) associated with conserved RAREs, suggesting these genes function downstream of RA. RA-regulated epigenetic marks were identified near RA target genes already known to be required for body axis and limb formation, thus validating our approach; plus, many other candidate RA target genes were found. Nuclear receptor 2f1 (Nr2f1) and nuclear receptor 2f2 (Nr2f2) in addition to Meis homeobox 1 (Meis1) and Meis homeobox 2 (Meis2) gene family members were identified by our approach, and double knockouts of each family demonstrated previously unknown requirements for body axis and/or limb formation. A similar epigenetic approach can be used to determine the target genes for any transcriptional regulator for which a knockout is available.
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Registered trials
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