From Pioneer to Repressor: Bimodal foxd3 Activity Dynamically Remodels Neural Crest Regulatory Landscape In Vivo
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Abstract
The neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from "permissive" to "repressive" nucleosome and chromatin organization to maintain multipotency and define cell fates.
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Both Foxd3 and Runx3 gene products can function as pioneer factors and both can activate or repress transcription depending on context.
“Intriguingly both gene products can function as pioneer factors and both can activate or repress transcription depending on context (50, 59).”
From Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish (2025) · cites this paper as [50]
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- Authors
- Lukoseviciute, M., Gavriouchkina, D., Williams, R. M., Hochgreb-Hagele, T., Senanayake, U., Chong-Morrison, V., Thongjuea, S., Repapi, E., Mead, A., & Sauka-Spengler, T.
- Affiliations
- University of Oxford (GB)
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 47
- Issue
- 5
- Pages
- 608-628.e6
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC6286384
- OpenAlex
- W2772957859
- Cited by
- 109
- References
- 9
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 7 · 2023: 15 · 2022: 12 · 2021: 30 · 2020: 11 · 2019: 15 · 2018: 5
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Research Explorer (The University of Manchester) (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by)
- Funders
- March of Dimes Foundation
- Medical Research Council (G0902418)
- Stavros Niarchos Foundation
- Leverhulme Trust (RPG-2015-026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- FOXD3, neural crest, transcriptional repressor, pioneer factors, chromatin organization, nucleosome remodeling, cis-regulatory elements, neural crest specification, neural crest migration, transcriptional regulatory networks, epigenomics, gene expression profiling, cell fate determination, multipotency
- MeSH terms
- Animals, Enhancer Elements, Genetic, Neural Crest, Zebrafish, Gene Expression Regulation, Developmental, Zebrafish Proteins, Chromatin Assembly and Disassembly, Forkhead Transcription Factors
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