@article{Kalna:2019:10.1161/CIRCRESAHA.118.313788,
author = {Kalna, V and Yang, Y and Peghaire, C and Frudd, K and hannah, R and Shah, A and Osuna, Almagro L and Boyle, J and gottgens, B and Ferrer, J and Randi, A and Birdsey, G},
doi = {10.1161/CIRCRESAHA.118.313788},
journal = {Circulation Research},
pages = {1337--1349},
title = {The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program},
url = {http://dx.doi.org/10.1161/CIRCRESAHA.118.313788},
volume = {124},
year = {2019}
}

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TY  - JOUR
AB  - 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-assoc
AU  - Kalna,V
AU  - Yang,Y
AU  - Peghaire,C
AU  - Frudd,K
AU  - hannah,R
AU  - Shah,A
AU  - Osuna,Almagro L
AU  - Boyle,J
AU  - gottgens,B
AU  - Ferrer,J
AU  - Randi,A
AU  - Birdsey,G
DO  - 10.1161/CIRCRESAHA.118.313788
EP  - 1349
PY  - 2019///
SN  - 0009-7330
SP  - 1337
TI  - The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program
T2  - Circulation Research
UR  - http://dx.doi.org/10.1161/CIRCRESAHA.118.313788
UR  - https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313788
UR  - http://hdl.handle.net/10044/1/69564
VL  - 124
ER  - 

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