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Open Access Highly Accessed Research article

Modifiers of notch transcriptional activity identified by genome-wide RNAi

Philippos Mourikis2, Robert J Lake3, Christopher B Firnhaber1 and Brian S DeDecker1*

Author Affiliations

1 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA

2 Stem Cells & Development, Department of Developmental Biology, Pasteur Institute, CNRS URA 2578, Paris, France

3 Epigenetics and Progenitor Cells Keystone Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA

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BMC Developmental Biology 2010, 10:107  doi:10.1186/1471-213X-10-107

Published: 19 October 2010

Abstract

Background

The Notch signaling pathway regulates a diverse array of developmental processes, and aberrant Notch signaling can lead to diseases, including cancer. To obtain a more comprehensive understanding of the genetic network that integrates into Notch signaling, we performed a genome-wide RNAi screen in Drosophila cell culture to identify genes that modify Notch-dependent transcription.

Results

Employing complementary data analyses, we found 399 putative modifiers: 189 promoting and 210 antagonizing Notch activated transcription. These modifiers included several known Notch interactors, validating the robustness of the assay. Many novel modifiers were also identified, covering a range of cellular localizations from the extracellular matrix to the nucleus, as well as a large number of proteins with unknown function. Chromatin-modifying proteins represent a major class of genes identified, including histone deacetylase and demethylase complex components and other chromatin modifying, remodeling and replacement factors. A protein-protein interaction map of the Notch-dependent transcription modifiers revealed that a large number of the identified proteins interact physically with these core chromatin components.

Conclusions

The genome-wide RNAi screen identified many genes that can modulate Notch transcriptional output. A protein interaction map of the identified genes highlighted a network of chromatin-modifying enzymes and remodelers that regulate Notch transcription. Our results open new avenues to explore the mechanisms of Notch signal regulation and the integration of this pathway into diverse cellular processes.