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Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization.

Abstract：

:Vascular endothelial growth factor A (VEGF-A) is a master regulator of angiogenesis, vascular development and function. In this study we investigated the transcriptional regulation of VEGF-A-responsive genes in primary human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) using genome-wide global run-on sequencing (GRO-Seq). We demonstrate that half of VEGF-A-regulated gene promoters are characterized by a transcriptionally competent paused RNA polymerase II (Pol II). We show that transition into productive elongation is a major mechanism of gene activation of virtually all VEGF-regulated genes, whereas only ∼40% of the genes are induced at the level of initiation. In addition, we report a comprehensive chromatin interaction map generated in HUVECs using tethered conformation capture (TCC) and characterize chromatin interactions in relation to transcriptional activity. We demonstrate that sites of active transcription are more likely to engage in chromatin looping and cell type-specific transcriptional activity reflects the boundaries of chromatin interactions. Furthermore, we identify large chromatin compartments with a tendency to be coordinately transcribed upon VEGF-A stimulation. We provide evidence that these compartments are enriched for clusters of regulatory regions such as super-enhancers and for disease-associated single nucleotide polymorphisms (SNPs). Collectively, these findings provide new insights into mechanisms behind VEGF-A-regulated transcriptional programs in endothelial cells.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Kaikkonen MU,Niskanen H,Romanoski CE,Kansanen E,Kivelä AM,Laitalainen J,Heinz S,Benner C,Glass CK,Ylä-Herttuala S

doi

10.1093/nar/gku1036

subject

Has Abstract

pub_date

2014-11-10 00:00:00

pages

12570-84

issue

20

eissn

0305-1048

issn

1362-4962

pii

gku1036

journal_volume

42

pub_type

杂志文章

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