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

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

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood Vessels / physiology*
  • DNA Methylation
  • Endothelial Cells / physiology*
  • Endothelium / physiology*
  • Epigenesis, Genetic*
  • Gene Expression Profiling*
  • Lung / physiology*
  • Mice
  • Smad6 Protein / metabolism
  • Smad7 Protein / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / biosynthesis

Substances

  • Smad6 Protein
  • Smad6 protein, mouse
  • Smad7 Protein
  • Smad7 protein, mouse
  • Transforming Growth Factor beta

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.