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Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA.
Man, H S Jeffrey; Sukumar, Aravin N; Lam, Gabrielle C; Turgeon, Paul J; Yan, Matthew S; Ku, Kyung Ha; Dubinsky, Michelle K; Ho, J J David; Wang, Jenny Jing; Das, Sunit; Mitchell, Nora; Oettgen, Peter; Sefton, Michael V; Marsden, Philip A.
Affiliation
  • Man HSJ; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Sukumar AN; Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
  • Lam GC; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Turgeon PJ; Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
  • Yan MS; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E2, Canada.
  • Ku KH; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
  • Dubinsky MK; Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
  • Ho JJD; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Wang JJ; Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
  • Das S; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Mitchell N; Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
  • Oettgen P; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Sefton MV; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Marsden PA; Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
Proc Natl Acad Sci U S A ; 115(10): 2401-2406, 2018 03 06.
Article de En | MEDLINE | ID: mdl-29467285
Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell type-specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for spliced-transcript endothelial-enriched lncRNA (STEEL) in angiogenic potential, macrovascular/microvascular identity, and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear enriched, and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse ECs. Of interest, STEEL up-regulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL up-regulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Chromatine / Néovascularisation physiologique / Cellules endothéliales / ARN long non codant Type d'étude: Prognostic_studies Limites: Animals / Humans Langue: En Journal: Proc Natl Acad Sci U S A Année: 2018 Type de document: Article Pays d'affiliation: Canada Pays de publication: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Chromatine / Néovascularisation physiologique / Cellules endothéliales / ARN long non codant Type d'étude: Prognostic_studies Limites: Animals / Humans Langue: En Journal: Proc Natl Acad Sci U S A Année: 2018 Type de document: Article Pays d'affiliation: Canada Pays de publication: États-Unis d'Amérique