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

Minna U. Kaikkonen, Henri Niskanen, Casey E. Romanoski, Emilia Kansanen, Annukka M. Kivelä, Jarkko Laitalainen, Sven Heinz, Christopher Benner, Christopher K. Glass, Seppo Ylä-Herttuala

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 endothe-lial 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.

Original languageEnglish (US)
Pages (from-to)12570-12584
Number of pages15
JournalNucleic acids research
Volume42
Issue number20
DOIs
StatePublished - Nov 10 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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