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Elife. 2018 May 11;7. pii: e34423. doi: 10.7554/eLife.34423.

The transcriptomic and epigenetic map of vascular quiescence in the continuous lung endothelium.

Author information

1
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
2
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
3
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
4
Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
5
Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Barcelona, Spain.
6
Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany.
7
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
8
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
9
Bioquant Center, Heidelberg University, Heidelberg, Germany.
10
German Cancer Consortium, Heidelberg, Germany.
#
Contributed equally

Abstract

Maintenance of a quiescent and organotypically-differentiated layer of blood vessel-lining endothelial cells (EC) is vital for human health. Yet, the molecular mechanisms of vascular quiescence remain largely elusive. Here we identify the genome-wide transcriptomic program controlling the acquisition of quiescence by comparing lung EC of infant and adult mice, revealing a prominent regulation of TGFß family members. These transcriptomic changes are distinctly accompanied by epigenetic modifications, measured at single CpG resolution. Gain of DNA methylation affects developmental pathways, including NOTCH signaling. Conversely, loss of DNA methylation preferentially occurs in intragenic clusters affecting intronic enhancer regions of genes involved in TGFβ family signaling. Functional experiments prototypically validated the strongly epigenetically regulated inhibitors of TGFβ family signaling SMAD6 and SMAD7 as regulators of EC quiescence. These data establish the transcriptional and epigenetic landscape of vascular quiescence that will serve as a foundation for further mechanistic studies of vascular homeostasis and disease-associated activation.

KEYWORDS:

DNA methylation; TGFß; computational biology; developmental biology; endothelial epigenome; endothelial quiescence; endothelial trsanscriptome; human; mouse; stem cells; systems biology

PMID:
29749927
PMCID:
PMC5947988
DOI:
10.7554/eLife.34423
[Indexed for MEDLINE]
Free PMC Article

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