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Cited by 119Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program

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Kalna, Viktoria, Yang, Youwen, Peghaire, Claire R., Frudd, Karen, Hannah, Rebecca, Shah, Aarti V., Osuna Almagro, Lourdes, Boyle, Joseph J. +4 more·2019·Circulation Research
DOI 10.1161/circresaha.118.313788PMC PMC6493686
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Abstract

Rationale: The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers). Objective: To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers. Methods and Results: Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4 (Delta-like protein 4), CLDN5 (claudin-5), VWF (von Willebrand factor), and CDH5 (VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-associated single nucleotide polymorphisms from genome-wide association studies lie within noncoding regions and perturb transcription factor recognition sequences in relevant cell types. Analysis of genome-wide association studies data shows significant enrichment of risk variants for cardiovascular disease and other diseases, at ERG endothelial enhancers and super-enhancers. Conclusions: The transcription factor ERG promotes endothelial homeostasis via regulation of lineage-specific enhancers and super-enhancers. Enrichment of cardiovascular disease-associated single nucleotide polymorphisms at ERG super-enhancers suggests that ERG-dependent transcription modulates disease risk.

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  • Genes possibly repressed by SOX9 include endothelial markers VWF and PECAM1, as well as genes encoding TFs important for endothelial cell functions, including ERG and ETS2.

    “Genes possibly repressed by SOX9 include endothelial markers, such as VWF and PECAM1, as well as genes encoding TFs important for endothelial cell functions, including ERG (60) and ETS2 (61).”

    From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [60]

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Authors
Kalna, V., Yang, Y., Peghaire, C. R., Frudd, K., Hannah, R., Shah, A. V., Osuna Almagro, L., Boyle, J. J., Göttgens, B., Ferrer, J., Randi, A. M., & Birdsey, G. M.
Affiliations
  • Imperial College London (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • From the National Heart and Lung Institute (V.K., Y.Y., C.R.P., K.F., A.V.S., L.O.A., J.J.B., A.M.R., G.M.B.), Imperial College London, United Kingdom
Corresponding author
  • Randi, Anna M.
  • Birdsey, Graeme M.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-04-26
Volume
124
Issue
9
Pages
1337-1349
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.118.313788
PMC
PMC6493686
OpenAlex
W2924079672
Cited by
119
References
7
Citations by year
2026: 12 · 2025: 18 · 2024: 13 · 2023: 21 · 2022: 17 · 2021: 23 · 2020: 11 · 2019: 2
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Circulation Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust (203151/Z/16/Z)
  • Cancer Research UK (21762)
  • British Heart Foundation (FS/13/12/30037, RG/11/17/29256, PG/17/33/32990, FS/15/65/32036, RG/17/4/32662)
  • Imperial College London
  • Medical Research Council (MC_PC_12009)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
ERG, super-enhancers, ETS transcription factors, H3K27ac, MED1, P300, GATA2, AP-1, DLL4, claudin-5, von Willebrand factor, VE-cadherin, TMPRSS2-ERG fusion, prostate cancer, enhancer regulation
MeSH terms
Transcriptional Regulator ERG, Cells, Cultured, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Male, Membrane Proteins, Prostatic Neoplasms, Serine Endopeptidases, Transcription Factor AP-1, Gene Expression Profiling, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, GATA2 Transcription Factor, Human Umbilical Vein Endothelial Cells, Claudin-5

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