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

Hui Wen Chen, Chang Ching Yang, Chia Ling Hsieh, Hsuan Liu, Sheng Chung Lee, Bertrand Chin Ming Tan

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1309-1319
Number of pages11
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1829
Issue number12
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

Keywords

  • ACVRL1
  • Angiogenesis
  • EDD
  • TGF-β
  • Transcriptional regulation
  • Ubiquitin E3 ligase

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Genetics
  • Molecular Biology
  • Structural Biology

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