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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1472-1478. Prepublished online as a Blood First Edition Paper on October 17, 2006; DOI 10.1182/blood-2006-08-039651. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-08-039651v1 109/4/1472    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Diehl, F. Articles by Urbich, C. Search for Related Content PubMed PubMed Citation Articles by Diehl, F. Articles by Urbich, C. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The histone methyltransferase MLL is an upstream regulator of endothelial-cell sprout formation Florian Diehl1, Lothar Rössig1, Andreas M. Zeiher1, Stefanie Dimmeler1, and Carmen Urbich1 1 Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Germany Posttranslational histone modification by acetylation or methylation regulates gene expression. Here, we investigated the role of the histone lysine methyltransferase MLL for angiogenic functions in human umbilical vein endothelial cells. Suppression of MLL expression by siRNA or incubation with the pharmacologic methyltransferase inhibitor 5'-deoxy-5'-(methylthio)adenosine significantly decreased endothelial-cell migration and capillary sprout formation, indicating that methyltransferase activity is required for proangiogenic endothelial-cell functions. Because the expression of homeodomain transcription factors (Hox) is regulated by MLL, we elucidated the role of Hox gene expression. MLL silencing was associated with reduced mRNA and protein expression of HoxA9 and HoxD3, whereas HoxB3, HoxB4, HoxB5, and HoxB9 were not altered. Overexpression of HoxA9 or HoxD3 partially compensated for impaired migration in MLL siRNA-transfected endothelial cells, suggesting that HoxA9 and HoxD3 both contribute to MLL-dependent migration. As a potential underlying mechanism, MLL siRNA down-regulated mRNA and protein levels of the HoxA9-dependent axon guidance factor EphB4. In contrast, MLL knockdown effects on capillary sprouting were not rescued by HoxA9 or HoxD3 overexpression, indicating that MLL affects additional targets required for 3-dimensional sprout formation. We conclude that MLL regulates endothelial-cell migration via HoxA9 and EphB4, whereas sprout formation requires MLL-dependent signals beyond HoxA9 and HoxD3. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. C. Matouk and P. A. Marsden Epigenetic Regulation of Vascular Endothelial Gene Expression Circ. Res., April 25, 2008; 102(8): 873 - 887. [Abstract] [Full Text] [PDF] S. Bandyopadhyay, M. Z. Ashraf, P. Daher, P. H. Howe, and P. E. DiCorleto HOXA9 Participates in the Transcriptional Activation of E-Selectin in Endothelial Cells Mol. Cell. Biol., June 15, 2007; 27(12): 4207 - 4216. [Abstract] [Full Text] [PDF]

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