TY - JOUR
T1 - A functional genomic approach reveals the transcriptional role of EDD in the expression and function of angiogenesis regulator ACVRL1
AU - Chen, Hui Wen
AU - Yang, Chang Ching
AU - Hsieh, Chia Ling
AU - Liu, Hsuan
AU - Lee, Sheng Chung
AU - Tan, Bertrand Chin Ming
N1 - Funding Information:
The present study was supported by the National Science Council of Taiwan ( NSC99-2632-B-182-001-MY3 , NSC101-2321-B-182-009 , and NSC101-2320-B-182-036-MY3 ), Chang Gung Memorial Hospital ( CMRPD1A0322 ), National Health Research Institute of Taiwan ( NHRI-EX101-9923SC ) and Ministry of Education, Taiwan .
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - ACVRL1
KW - Angiogenesis
KW - EDD
KW - TGF-β
KW - Transcriptional regulation
KW - Ubiquitin E3 ligase
UR - http://www.scopus.com/inward/record.url?scp=84888069418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84888069418&partnerID=8YFLogxK
U2 - 10.1016/j.bbagrm.2013.10.006
DO - 10.1016/j.bbagrm.2013.10.006
M3 - Article
C2 - 24189493
AN - SCOPUS:84888069418
SN - 1874-9399
VL - 1829
SP - 1309
EP - 1319
JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
IS - 12
ER -