title: A functional genomic approach reveals the transcriptional role of EDD in the expression and function of angiogenesis regulator ACVRL1.
abstract: EDD (E3 isolated by differential display) was initially isolated as a progestin-regulated gene in breast cancer cells, and represents the human ortholog of the Drosophila melanogaster hyperplastic discs gene (hyd). It encodes a highly conserved and predominantly nuclear ubiquitin E3 ligase of the HECT family, with potential multifunctional roles in development and tumorigenesis. In this study, we further examined the largely uncharacterized role of EDD in transcriptional regulation by uncovering the spectrum of its direct target genes at a genome-wide level. Use of a systematic approach that integrates gene expression and chromatin binding profiling identified several candidate EDD-target genes, one of which is ACVRL1, a TGF-β receptor with functional implications in blood vessel development. Further characterization revealed a negative regulation of ACVRL1 gene expression by EDD that is exerted at the promoter. Consistent with the aberrant upregulation of ACVRL1 and downstream Smad signaling, abrogation of EDD led to deregulated vessel development and endothelial cell motility. Collectively, these results extended the known cellular roles of EDD to critical functions in transcriptional regulation as well as angiogenesis, and may provide mechanistic explanations for EDD's tumorigenic and developmental roles.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Chang-Ching
authors.initials: CC
authors.lastname: Yang
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Hsieh
authors.forename: Hsuan
authors.initials: H
authors.lastname: Liu
authors.forename: Sheng-Chung
authors.initials: SC
authors.lastname: Lee
authors.forename: Bertrand Chin-Ming
authors.initials: BC
authors.lastname: Tan
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement; D002633:Chemotaxis; D047369:Chromatin Immunoprecipitation; D019084:Fluorescent Antibody Technique, Indirect; D023281:Genomics; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D008156:Luciferases; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: ACVRL1; Angiogenesis; ChIP; E3 isolated by differential display; EDD; HUVEC; TGF-β; Transcriptional regulation; Ubiquitin E3 ligase; activin receptor-like kinase 1; chromatin immunoprecipitation; human umbilical vein endothelial cell; shRNA; short hairpin RNA; siRNA; small interfering RNA; transforming growth factor-β