A Transcription Factor Collective Defines Cardiac Cell Fate and Reflects Lineage History
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Cell fate decisions are driven through the integration of inductive signals and tissue-specific transcription factors (TFs), although the details on how this information converges in cis remain unclear. Here, we demonstrate that the five genetic components essential for cardiac specification in Drosophila, including the effectors of Wg and Dpp signaling, act as a collective unit to cooperatively regulate heart enhancer activity, both in vivo and in vitro. Their combinatorial binding does not require any specific motif orientation or spacing, suggesting an alternative mode of enhancer function whereby cooperative activity occurs with extensive motif flexibility. A fraction of enhancers co-occupied by cardiogenic TFs had unexpected activity in the neighboring visceral mesoderm but could be rendered active in heart through single-site mutations. Given that cardiac and visceral cells are both derived from the dorsal mesoderm, this "dormant" TF binding signature may represent a molecular footprint of these cells' developmental lineage.
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The TF collective model was originally formulated in Drosophila, where a set of five transcription factors bound multitudes of enhancers required for heart development that showed no detectable similarity in their sequence organisation beyond the presence of binding motifs for some of these transcription factors.
“The TF collective model was originally formulated in Drosophila, where a set of five TFs bound multitudes of enhancers required for heart development that showed no detectable similarity in their sequence organisation, beyond the presence of binding motifs for some of these TFs [91].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [91]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe TF collective model proposes that a set of the same transcription factors binds to multiple enhancers but an individual enhancer does not necessarily have the full set of transcription factor binding sites.
“An intermediate model for enhancer grammar known as the “TF collective” proposes that a set of the same TFs binds to multiple enhancers but an individual enhancer does not necessarily have the full set of TF binding sites [30, 91].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [91]
Later studies of Drosophila developmental enhancers found evidence for much less rigid motif organisation.
“In contrast, later studies of Drosophila developmental enhancers found evidence for much less rigid motif organisation [90, 91].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [91]
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- Authors
- Junion, G., Spivakov, M., Girardot, C., Braun, M., Gustafson, E. H., Birney, E., & Furlong, E. E. M.
- Affiliations
- European Molecular Biology Laboratory (DE)
- European Bioinformatics Institute (GB)
- Corresponding author
- Furlong, Eileen E.M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 148
- Issue
- 3
- Pages
- 473-486
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2086876386
- Cited by
- 257
- References
- 79
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 16 · 2023: 7 · 2022: 14 · 2021: 30 · 2020: 18 · 2019: 10 · 2018: 12 · 2017: 17 · 2016: 23 · 2015: 18 · 2014: 31 · 2013: 34 · 2012: 12
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 532 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- 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
- cardiac specification, transcription factors, enhancer regulation, Dpp signaling, Drosophila heart development, dorsal mesoderm, lineage history, visceral mesoderm, point mutations, cis-regulatory elements
- MeSH terms
- Animals, Drosophila melanogaster, Enhancer Elements, Genetic, Mesoderm, Myocardium, Transcription Factors, Gene Expression Regulation, Developmental, Drosophila Proteins, Gene Regulatory Networks
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