Evaluating the transcriptional regulators of arterial gene expression via a catalogue of characterized arterial enhancers

Abstract
Data availability
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Abstract

The establishment and growth of the arterial endothelium requires the coordinated expression of numerous genes. However, regulation of this process is not yet fully understood. Here, we combined in silico analysis with transgenic mice and zebrafish models to characterize arterial-specific enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1 and Unc5b). Next, to elucidate the regulatory pathways upstream of arterial gene transcription, we investigated the transcription factors binding each arterial enhancer compared to a similar assessment of non-arterial endothelial enhancers. These results found that binding of SOXF and ETS factors was a common occurrence at both arterial and pan-endothelial enhancers, suggesting neither are sufficient to direct arterial specificity. Conversely, FOX motifs independent of ETS motifs were over-represented at arterial enhancers. Further, MEF2 and RBPJ binding was enriched but not ubiquitous at arterial enhancers, potentially linked to specific patterns of behaviour within the arterial endothelium. Lastly, there was no shared or arterial-specific signature for WNT-associated TCF/LEF, TGFβ/BMP-associated SMAD1/5 and SMAD2/3, shear stress-associated KLF4 or venous-enriched NR2F2. This cohort of well characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signalling pathways with arterial gene expression.

Data availability

Cut&Run data for Sox7, Sox17 and Sox 18 have been deposited at GEO under the accession number GSE283369

The following data sets were generated

1. Susann Bruche
2. Sarah De Val
(2024) SOX7, SOX17 and SOX18 DNA binding in baseline HUVEC
GEO GSE283369.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE283369

The following previously published data sets were used

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6. Vellarikkal SK
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Article and author information

Author details

Svanhild Nornes

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5301-5252
Susann Bruche

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5814-7166
Niharika Adak

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Ian R McCracken

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Sarah De Val

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

For correspondence
Sarah.deval@dpag.ox.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2566-2348

Funding

British Heart Foundation (FS/1735/32929)

Sarah De Val

British Heart Foundation (FS/1735/32929)

Svanhild Nornes

British Heart Foundation (FS/SBSRF/22/31037)

Svanhild Nornes

British Heart Foundation (FS/SBSRF/22/31037)

Sarah De Val

British Heart Foundation (FS/IPBSRF/23/27085)

Ian R McCracken

British Heart Foundation (RE/18/3/34214)

Sarah De Val

Fondation Leducq (18CVD03)

Susann Bruche

Ludwig Institute for Cancer Research

Sarah De Val

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were approved by a local ethical review committee at Oxford University and licensed by the UK Home Office, license number PP1224162.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.