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Cited by 142Genomics and Chromatin DynamicsRetinoids in leukemia and cellular processesPluripotent Stem Cells Research

Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis

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Mahony, Shaun, Mazzoni, Esteban O, McCuine, Scott, Young, Richard A, Wichterle, Hynek, Gifford, David K·2011·Genome Biology
DOI 10.1186/gb-2011-12-1-r2PMC PMC3091300
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Abstract

Background: Among its many roles in development, retinoic acid determines the anterior-posterior identity of differentiating motor neurons by activating retinoic acid receptor (RAR)-mediated transcription. RAR is thought to bind the genome constitutively, and only induce transcription in the presence of the retinoid ligand. However, little is known about where RAR binds to the genome or how it selects target sites. Results: We tested the constitutive RAR binding model using the retinoic acid-driven differentiation of mouse embryonic stem cells into differentiated motor neurons. We find that retinoic acid treatment results in widespread changes in RAR genomic binding, including novel binding to genes directly responsible for anterior-posterior specification, as well as the subsequent recruitment of the basal polymerase machinery. Finally, we discovered that the binding of transcription factors at the embryonic stem cell stage can accurately predict where in the genome RAR binds after initial differentiation. Conclusions: We have characterized a ligand-dependent shift in RAR genomic occupancy at the initiation of neurogenesis. Our data also suggest that enhancers active in pluripotent embryonic stem cells may be preselecting regions that will be activated by RAR during neuronal differentiation.

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  • The occupancy of several promoters by RAR/RXR heterodimers is increased in response to RA.

    “Such a mechanism might be at the basis of the observation made by several laboratories that the occupancy of several promoters by RAR/RXR heterodimers is increased in response to RA ( 80,82,96 ).”

    From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [80]

    The Results section, “A compact retinoid response is directly mediated by RAR” (page unavailable), reports genes with RAR binding detected only after RA exposure, supporting increased occupancy at some sites. But the study measured RAR occupancy, not specifically RAR/RXR heterodimers, and describes those sites as near genes rather than establishing increased occupancy at their promoters. The Results section on RNA polymerase II initiation also says several named RA-responsive genes were constitutively bound by RAR. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Recent genome-wide ChIP-seq technology allowed the identification of new RAR-binding loci and expanded the repertoire of potential high-affinity response elements.

    “Most interestingly, the recent genome wide ChIP-seq (chromatin immunoprecipitation coupled with deep sequencing) technology allowed the identifi cation of new RAR-binding loci and expanded the repertoire of potential high-affi nity response elements (80)(81)(82).”

    From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [80]

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Authors
Mahony, S., Mazzoni, E. O., McCuine, S., Young, R. A., Wichterle, H., & Gifford, D. K.
Affiliations
  • Massachusetts Institute of Technology (US)
  • Columbia University Irving Medical Center (US)
  • Whitehead Institute for Biomedical Research (US)
  • MIT Computer Science and Artificial Intelligence Laboratory (US)
Corresponding author
Gifford, David K
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2011-01-13
Volume
12
Issue
1
Pages
R2-R2
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2011-12-1-r2
PMC
PMC3091300
OpenAlex
W2132437126
Cited by
142
References
5
Citations by year
2026: 4 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 12 · 2020: 5 · 2019: 10 · 2018: 14 · 2017: 8 · 2016: 9 · 2015: 14 · 2014: 23 · 2013: 17 · 2012: 5
FWCI
6.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • Columbia Academic Commons (Columbia University)
Funders
  • Damon Runyon Cancer Research Foundation
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (P01NS055923)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
retinoic acid receptor, retinoic acid, ligand-dependent transcription, motor neuron differentiation, neurogenesis, embryonic stem cells, enhancers, transcription factor binding, basal transcription machinery, transcriptional regulation
MeSH terms
Cell Differentiation, DNA-Binding Proteins, Gene Expression Regulation, Ligands, Protein Binding, RNA Polymerase II, Transcription, Genetic, Tretinoin, Receptors, Retinoic Acid, Gene Expression Profiling, Embryonic Stem Cells, Neurogenesis

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