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And Karl Stangl Henryk Dreger, Antje Ludwig, Andrea Weller, Verena Epigenetic Regulation of Cell Adhesion and Communication by Enhancer of Zeste Homolog 2 in Human Endothelial Cells Henryk Dreger, Antje Ludwig, Andrea Weller, Verena Stangl, Gert Baumann, Silke Meiners and Karl Stangl Hypertension. published online September 10, 2012; Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2012 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/early/2012/09/10/HYPERTENSIONAHA.112.191098 Data Supplement (unedited) at: http://hyper.ahajournals.org/content/suppl/2012/09/10/HYPERTENSIONAHA.112.191098.DC1.html Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/ Downloaded from http://hyper.ahajournals.org/ by guest on September 11, 2012 Original Article Epigenetic Regulation of Cell Adhesion and Communication by Enhancer of Zeste Homolog 2 in Human Endothelial Cells Henryk Dreger, Antje Ludwig, Andrea Weller, Verena Stangl, Gert Baumann, Silke Meiners*, Karl Stangl* Abstract—The histone methyltransferase enhancer of zeste homolog 2 (Ezh2) mediates trimethylation of lysine 27 in histone 3, which acts as a repressive epigenetic mark. Ezh2 is essential for maintaining pluripotency of stem cells, but information on its role in differentiated cells is sparse. Whole-genome mRNA expression arrays identified 964 genes that were regulated by >2-fold 72 hours after small interfering RNA-mediated silencing of Ezh2 in human umbilical vein endothelial cells. Among them, genes associated with the gene ontology terms cell communication and cell adhesion were significantly overrepresented, suggesting a functional role for Ezh2 in the regulation of angiogenesis. Indeed, adhesion, migration, and tube formation assays revealed significantly altered angiogenic properties of human umbilical vein endothelial cells after silencing of Ezh2. To identify direct target genes of Ezh2, we performed chromatin immunoprecipitation experiments followed by whole-genome promoter arrays (chromatin immunoprecipitation-on-chip) and identified 5585 genes associated with trimethylation of lysine 27 in histone 3. Comparative analysis with our mRNA expression data identified 276 genes that met our criteria for putative Ezh2 target genes, upregulation by >2-fold after Ezh2 silencing and association with trimethylation of lysine 27 in histone 3. Notably, we observed a striking overrepresentation of genes involved in wingless-type mouse mammary tumor virus integration site (WNT) signaling pathways. Epigenetic regulation of several of these genes by Ezh2 was specifically confirmed by polymerase chain reaction analysis of DNA enrichment after chromatin immunoprecipitation using an antibody specific for trimethylation of lysine 27 in histone 3. Combining mRNA expression arrays and chromatin immunoprecipitation-on-chip analysis, we identified 276 Ezh2 target genes in endothelial cells. Ezh2-dependent repression of genes involved in cell adhesion and communication contributes to the regulation of angiogenesis. (Hypertension. 2012;60:00-00.) ● Online Data Supplement Key Words: enhancer of zeste homolog 2 ◼ epigenetics ◼ angiogenesis ◼ histone methylation ◼ cell communication ◼ cell adhesion ◼ wingless-type MMTV-integration site signaling pigenetic modifications, such as DNA and histone meth- thereby relieving repression of PRC target genes and thus Eylation, have long-term effects on gene expression. contributing to target gene activation.3,4 In tissue-specific The histone methyltransferase enhancer of zeste homolog differentiation studies, Ezh2 was shown to play a crucial role 2 (Ezh2) mediates trimethylation of lysine 27 of histone 3 in heart development, neurogenesis, skeletal muscle differ- (H3K27me3), which acts as a repressive epigenetic mark.1 entiation, and adipogenesis, as well as in the generation of Ezh2 belongs to the Polycomb group proteins that are epidermal progenitor cells.4–8 well-characterized regulators of the epigenome. These pro- In addition to stem cells, cancer cells have been shown to teins were first identified in Drosophila, where they form express high levels of Ezh2, which is associated with poor Polycomb repressive complexes (PRC) and suppress homeo- outcome.9,10 Among other mechanisms, this has been attributed tic genes responsible for segment identity.2 PRCs are highly to Ezh2-mediated silencing of vasoinhibin-1 and subsequent conserved also in humans and have been shown to be essen- promotion of angiogenesis.10 In contrast, little is known tial for maintaining pluripotency by repression of develop- about Ezh2 target genes in differentiated cells. Interestingly, mental genes in human stem cells.2,3 During differentiation, transcriptomic studies on cells and tissues suggest a relatively expression of PRC subunits, among them Ezh2, decreases, high expression of Ezh2 in endothelial cells.11 Furthermore, Received January 9, 2012; first decision February 3, 2012; revision accepted August 8, 2012. From the Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charité – Universitätsmedizin Berlin, Berlin, Germany (H.D., A.L., A.W., V.S., G.B., K.S.); and Comprehensive Pneumology Center, Ludwig-Maximilians-Universität, Asklepios Fachkliniken München-Gauting and Helmholtz Zentrum München, München, Germany (S.M.). *These authors contributed equally to this work. The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi: 10.1161/HYPERTENSIONAHA. 112.191098/-/DC1. Correspondence to Henryk Dreger, Medizinische Klinik für Kardiologie und Angiologie, Charité – Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. E-mail [email protected] © 2012 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI:10.1161/HYPERTENSIONAHA.112.191098 Downloaded from http://hyper.ahajournals.org/1 by guest on September 11, 2012 2 Hypertension November 2012 a recent study demonstrated that the migratory properties Tube Formation Assays of endothelial cells are altered by microRNA-mediated Seventy-two hours after siRNA transfection, HUVECs were trans- inhibition of Ezh2.12 These data indicate a role for Ezh2- ferred to 24-well plates that had been prepared with 230 µL of matri- dependent epigenetic control of endothelial cell function gel per well (Basement Membrane Matrix Phenol Red Free; BD in vessel formation and angiogenesis. In addition, studies Biosciences, Heidelberg, Germany). After 23 hours, 5 digital pictures were taken per well, and tube formation was subsequently analyzed on the Hutchinson–Gilford progeria syndrome suggest that in a blinded fashion using a commercial imaging service (Wimasis accelerated atherosclerosis—a hallmark of this childhood GmbH, Munich, Germany). disease—is caused, at least in part, by a loss of epigenetic control, including a deficit of repressive epigenetic marks Migration Assay such as H3K27me3.13 To assess cell migration, we performed scratch assays. The cell-free Taken together, there is growing evidence for a physiologi- area was digitally quantified (Photoshop; Adobe Systems, Inc) imme- cal role of Ezh2 in differentiated endothelial cells. The aim of diately, as well as 16 hours after scraping the cell monolayer with a 17 our present study was to further elucidate the function of Ezh2 pipette tip. by identification of its target genes in endothelial cells. Adhesion Assay Methods After blocking with 0.5% BSA (Sigma) in PBS, 5×104 cells were incubated in fibronectin-coated 24-well plates (BD Biosciences) Detailed information on materials and methods are provided in the for 1 hour at 37°C. Subsequently, plates were agitated at 400 revo- online-only Data Supplement. lutions per minute for 15 seconds. After washing, adherent cells were fixed with paraformaldehyde and stained using 0.1% crystal Cell Culture violet (Sigma). Finally, absorption was quantified after adding 10% Human umbilical vein endothelial cells (HUVECs) from different acetic acid at 570 nm. donors were prepared and kept in culture, as described previously.14 The cell preparation conformed to local university ethics guidelines Chromatin Immunoprecipitation and the principles outlined in the Declaration of Helsinki. Chromatin immunoprecipitation (ChIP) was performed accord- 18 Small Interfering RNA Transfections and mRNA ing to a protocol published by Dahl et al, with minor modifica- tions using an H3K27me3 antibody (ab6002; Abcam, Cambridge, Expression Analysis United Kingdom) or an unspecific mouse IgG (sc2025; Santa Cruz, Cells were transfected with 25 nmol/L of control small interfer- Heidelberg, Germany). Purified DNA was either used for ChIP-PCR ing RNA (siRNA) (Silencer Select Negative
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