Linking Transcriptional Regulation and Cell Growth/Differentiation---An Integrated Functional Genomic Approach to Characterizing the Transcriptional Role of EDD

EDD (E3 isolated by differential display), the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), was originally identified as a progestin-regulated gene in human breast cancer cells. As a HECT domain-containing protein, EDD may be involved in the signaling cascade that catalyzes the covalent attachment of ubiquitin to specific substrate. Although mammalian EDD has putatively been implicated in cell proliferation and linked to tumorigenesis, its exact cellular role and mode of action are largely uncharacterized. Recent findings have identified a potential but mostly indefinable role of EDD in transcriptional regulation. In this proposal, we hope to further explore this function by undertaking an integrated and systematic approach, entailing methods such as ChIP-on-chip, microarray, and TF-TF array analyses. First, we aim to achieve a global identification of EDD’s transcriptional targets by using a combination of two powerful screening methods, chromatin immunoprecipitation and gene expression profiling at the genomic level. Next, to delineate the molecular mechanism underlying EDD-orchestrated transcriptional regulation, we will characterize three different, but not mutually exclusive, functional attributes of EDD: associated transcriptional coregulators, downstream ubiquitination substrates linked to transcription, and promoter-associated epigenetic regulation. Finally, physiological relevance and significance of the EDD transcriptional network can be illustrated by assessing possible alteration of such network during 1) tumorigenesis and 2) Drosophila embryonic development, as well as tumorigenic and developmental association of the corresponding EDD targets. The experimental system established in this proposal will advance our functional and mechanistic understanding of EDD’s transcriptional roles and further expand our view on the link between gene expression regulation (or misregulation) and cellular metabolism.A

Project ID:PC9709-0937
External Project ID:NSC97-2320-B182-027-MY3