Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA
| Autor: | Peter Oettgen, Aravin N. Sukumar, H. S. Jeffrey Man, Matthew Yan, Michelle K. Dubinsky, Gabrielle C. Lam, J.J. David Ho, Paul J. Turgeon, Jenny Wang, Nora Mitchell, Sunit Das, Kyung Ha Ku, Michael V. Sefton, Philip A. Marsden |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Angiogenesis Neovascularization Physiologic Mice SCID 030204 cardiovascular system & hematology 03 medical and health sciences Mice 0302 clinical medicine Enos Transcriptional regulation Human Umbilical Vein Endothelial Cells Animals Humans Gene Transcription factor Cells Cultured Multidisciplinary biology Hemodynamics RNA Endothelial Cells Biological Sciences biology.organism_classification Long non-coding RNA Chromatin Cell biology 030104 developmental biology KLF2 RNA Long Noncoding Endothelium Vascular |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 115(10) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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