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      A functional genomic approach reveals the transcriptional role of EDD in the expression and function of angiogenesis regulator ACVRL1.

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          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.

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          Author and article information

          Journal
          Biochim. Biophys. Acta
          Biochimica et biophysica acta
          0006-3002
          0006-3002
          Dec 2013
          : 1829
          : 12
          Affiliations
          [1 ] 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.
          Article
          S1874-9399(13)00155-7
          10.1016/j.bbagrm.2013.10.006
          24189493
          0475fb95-e849-46ed-a8c8-cea5ffd9154b
          © 2013.
          History

          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

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