The transcriptomic and epigenetic map of vascular quiescence in the continuous lung endothelium
Katharina Schlereth,
Dieter Weichenhan,
Tobias Bauer,
Tina Heumann,
Evangelia Giannakouri,
Daniel Lipka,
Samira Jaeger,
Matthias Schlesner,
Patrick Aloy,
Roland Eils,
Christoph Plass,
Hellmut G Augustin
Affiliations
Katharina Schlereth
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
Dieter Weichenhan
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany
Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany
Tina Heumann
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
Evangelia Giannakouri
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany
Samira Jaeger
Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Barcelona, Spain
Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany
Patrick Aloy
Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
Roland Eils
Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany; Bioquant Center, Heidelberg University, Heidelberg, Germany
Christoph Plass
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany
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.