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

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...

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Main Authors:	Kaikkonen, Minna U., Niskanen, Henri, Romanoski, Casey E., Kansanen, Emilia, Kivelä, Annukka M., Laitalainen, Jarkko, Heinz, Sven, Benner, Christopher, Glass, Christopher K., Ylä-Herttuala, Seppo
Format:	Online
Language:	English
Published:	Oxford University Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227755/

id	pubmed-4227755
recordtype	oai_dc
spelling	pubmed-42277552014-11-21 Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization Kaikkonen, Minna U. Niskanen, Henri Romanoski, Casey E. Kansanen, Emilia Kivelä, Annukka M. Laitalainen, Jarkko Heinz, Sven Benner, Christopher Glass, Christopher K. Ylä-Herttuala, Seppo Gene regulation, Chromatin and Epigenetics 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. Oxford University Press 2014-11-10 2014-10-28 /pmc/articles/PMC4227755/ /pubmed/25352550 http://dx.doi.org/10.1093/nar/gku1036 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kaikkonen, Minna U. Niskanen, Henri Romanoski, Casey E. Kansanen, Emilia Kivelä, Annukka M. Laitalainen, Jarkko Heinz, Sven Benner, Christopher Glass, Christopher K. Ylä-Herttuala, Seppo
spellingShingle	Kaikkonen, Minna U. Niskanen, Henri Romanoski, Casey E. Kansanen, Emilia Kivelä, Annukka M. Laitalainen, Jarkko Heinz, Sven Benner, Christopher Glass, Christopher K. Ylä-Herttuala, Seppo Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization
author_facet	Kaikkonen, Minna U. Niskanen, Henri Romanoski, Casey E. Kansanen, Emilia Kivelä, Annukka M. Laitalainen, Jarkko Heinz, Sven Benner, Christopher Glass, Christopher K. Ylä-Herttuala, Seppo
author_sort	Kaikkonen, Minna U.
title	Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization
title_short	Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization
title_full	Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization
title_fullStr	Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization
title_full_unstemmed	Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization
title_sort	control of vegf-a transcriptional programs by pausing and genomic compartmentalization
description	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.
publisher	Oxford University Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227755/
_version_	1613155054739521536

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

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