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Angiogenic Patterning by STEEL, an Endothelial-Enriched Long Angiogenic patterning by STEEL, an endothelial- enriched long noncoding RNA H. S. Jeffrey Mana,b, Aravin N. Sukumara,b, Gabrielle C. Lamc,d, Paul J. Turgeonb,e, Matthew S. Yanb,f, Kyung Ha Kub,e, Michelle K. Dubinskya,b, J. J. David Hob,f, Jenny Jing Wangb,e, Sunit Dasg,h, Nora Mitchelli, Peter Oettgeni, Michael V. Seftonc,d,j, and Philip A. Marsdena,b,e,f,1 aInstitute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; bKeenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada; cDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E2, Canada; dInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; eDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; fDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; gArthur and Sonia Labatt Brain Tumour Research Institute, Hospital for SickKids, University of Toronto, Toronto, ON M5G 1X8, Canada; hDivision of Neurosurgery and Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada; iDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; and jDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada Edited by Napoleone Ferrara, University of California, San Diego, La Jolla, CA, and approved January 24, 2018 (received for review August 28, 2017) Endothelial cell (EC)-enriched protein coding genes, such as endothelial formation in vitro and blood vessel formation in vivo. STEEL nitric oxide synthase (eNOS), define quintessential EC-specific physio- regulates transcription of a key mediator of local blood flow, logic functions. It is not clear whether long noncoding RNAs (lncRNAs) endothelial nitric oxide synthase (eNOS), and a key sensor of also define cardiovascular cell type-specific phenotypes, especially in hemodynamic forces, Kruppel-like factor 2 (KLF2). The STEEL the vascular endothelium. Here, we report the existence of a set of EC- RNA forms a ribonucleoprotein complex with poly(ADP-ribose) enrichedlncRNAsanddefinearoleforspliced-transcript endothelial- polymerase 1 (PARP1) that targets PARP1 to the KLF2 and enriched lncRNA (STEEL) in angiogenic potential, macrovascular/ eNOS promoters. We argue that feedback inhibition regulates microvascular identity, and shear stress responsiveness. STEEL is STEEL expression to modulate angiogenic behavior in a vascular expressed from the terminus of the HOXD locus and is transcribed tree position-dependent and shear-dependent fashion. antisense to HOXD transcription factors. STEEL RNA increases the num- ber and integrity of de novo perfused microvessels in an in vivo model Results and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, Cell Type-Specific Expression of lncRNAs and Protein-Coding mRNAs nuclear enriched, and has microvascular predominance. Functionally, in Human Primary Cells. Six primary human cell types [human STEEL regulates a number of genes in diverse ECs. Of interest, STEEL umbilical vein ECs (HUVECs), human dermal microvascular up-regulates both eNOS and the transcription factor Kruppel-like factor ECs (HMVECs), human aortic smooth muscle cells (HASMCs), 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear- hepatocytes, dermal fibroblasts, and epidermal keratinocytes] augmented KLF2. Mechanistically, STEEL up-regulation of eNOS and from multiple independent donors were profiled, in parallel, for CELL BIOLOGY KLF2 is transcriptionally mediated, in part, via interaction of chromatin- associated STEEL with the poly-ADP ribosylase, PARP1. For instance, Significance 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 Endothelial cells (ECs) form the inner cellular lining of blood for lncRNAs in the transcriptional regulation of EC identity. vessels and are necessary in the establishment and mainte- nance of the closed cardiovascular system, especially the physiology of regulated blood flow to and from tissues. Re- long noncoding RNA | endothelium | angiogenesis | hemodynamics | chromatin cently, long noncoding RNAs (lncRNAs) have been described to have roles in gene regulation for a variety of processes, in- cluding stem cell functions and differentiation of stem cells into better understanding of how endothelial cells (ECs) acquire tissues. This work identifies lncRNAs that are enriched in ECs and Adistinct phenotypes is a prerequisite for treatment of vas- further characterizes the lncRNA, spliced-transcript endothelial- cular diseases and for regenerative medicine purposes. EC- enriched lncRNA (STEEL). STEEL promotes the formation of intact enriched genes are major determinants of specialized EC func- blood vessels by ECs in vivo. Moreover, STEEL regulates tran- tions that coordinate EC phenotype to functional context such as scription of a key mediator of local blood flow, endothelial nitric microvascular versus macrovascular function (1). oxide synthase (eNOS), and a key sensor of hemodynamic Recent evidence from genome-wide transcription analysis sug- forces, Kruppel-like factor 2 (KLF2). gests that long noncoding RNAs (lncRNAs) play important roles – in controlling cellular phenotype (2 4) and in pathogenesis of Author contributions: H.S.J.M. and P.A.M. designed research; H.S.J.M., A.N.S., G.C.L., disease, including cancer and cardiovascular disease (4, 5). Still, P.J.T., M.S.Y., K.H.K., M.K.D., J.J.D.H., J.J.W., N.M., and P.O. performed research; M.V.S. only few cell type-enriched lncRNAs have been functionally contributed new reagents/analytic tools; H.S.J.M., A.N.S., G.C.L., P.J.T., M.S.Y., K.H.K., characterized (2). Though some lncRNAs are tissue specific (2), M.K.D., S.D., M.V.S., and P.A.M. analyzed data; and H.S.J.M. and P.A.M. wrote the paper. others, such as the lncRNA MALAT1, are widely expressed and The authors declare no conflict of interest. serve core cellular functions in multiple cell types (6). In ECs, This article is a PNAS Direct Submission. many of the genes that define endothelial phenotype, including Published under the PNAS license. control of vasomotor tone, response to shear stress, and formation Data deposition: The data reported in this paper have been deposited in the Gene Expres- of new blood vessels, are expressed in an EC-enriched fashion (1). sion Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE108321). Of interest, EC-enriched lncRNAs have yet to be described. We The mass spectrometry proteomics data have been deposited to the ProteomeXchange sought to identify EC-enriched lncRNAs that could contribute to Consortium via the PRIDE partner repository with the dataset identifier PXD008581. the phenotypic plasticity of ECs in their unique environment. 1To whom correspondence should be addressed. Email: [email protected]. In this study, we describe a set of EC-enriched lncRNAs and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. functionally characterize spliced-transcript endothelial-enriched 1073/pnas.1715182115/-/DCSupplemental. lncRNA (STEEL). We demonstrate that STEEL promotes network Published online February 21, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1715182115 PNAS | March 6, 2018 | vol. 115 | no. 10 | 2401–2406 Downloaded by guest on September 29, 2021 the expression of lncRNAs and protein-coding genes using cus- mRNAs enriched uniquely in either HUVECs or HMVECs, re- tom lncRNA microarrays representing 23,155 putative lncRNAs spectively (SI Appendix, Fig. S1D). EC-enriched protein-coding and 19,484 protein-coding genes (Fig. 1 A–C, SI Appendix, Figs. genes including VE-cadherin, vWF, and CD31/PECAM1 (1) are S1 and S2, and Dataset S1). Of those, 18,524 lncRNAs and highly EC enriched on the microarrays (SI Appendix,Fig.S2B–D). 18,701 protein-coding genes were expressed above the 20th We verified representative EC-enriched lncRNAs that were highly percentile in at least one cell type and were considered for enriched and abundant, spliced, did not have sense overlap with further analysis. A total of 2,974 lncRNAs (16.1%) and 5,276 protein-coding genes, and were near EC-enriched protein- protein-coding genes (28.2%) were differentially expressed across coding genes. HHIP-AS1, FLI-AS1, LOC100505812/CARD8-AS, cell types. Consistent with this observation, unsupervised cluster- AF161442/HSPC324, and STEEL (SI Appendix,Fig.S3)are ing using Pearson centered correlation revealed cell type-based lncRNAs transcribed antisense to and nonoverlapping with EC- patterns of expression for both lncRNAs and protein-coding enriched genes HHIP1, FLI1, CARD8, EGFL7, and HOXD1 mRNAs (Fig. 1A and SI Appendix,Fig.S2A). (Dataset S1) (1). We also defined a group of “EC exempt” lncRNAs and protein-coding mRNAs as those whose expression Identification of Endothelial-Enriched lncRNAs. HUVEC and HMVEC was decreased by greater than fourfold in both HUVECs and lncRNAs and protein-coding genes cluster on heatmap and prin- A B SI Appendix HMVECs versus each of the other four cell types. This analysis cipal component analyses (Fig. 1 and and ,Figs. identified 25 lncRNAs and 113 protein-coding mRNAs as EC S1A and S2A). We defined EC-enriched lncRNAs as those that SI Appendix SI Appendix B exempt ( ,Fig.S4and Dataset S2). Whether any of were enriched greater than fourfold ( ,Fig.S1 )inei- these lncRNAs silence EC-enriched genes in other cell types, ther HUVECs or HMVECs versus each of the four non-EC types, similar to the RE-1 silencing transcription factor, which silences with significance by one-way ANOVA. This analysis yielded 116 neuronal genes in nonneuronal cells (7), requires further study. EC-enriched lncRNAs: 29 EC-enriched lncRNAs in common be- tween HUVECs and HMVECs, 28 and 59 enriched uniquely in D STEEL Is an Endothelial-Enriched lncRNA.
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