Abstract SY15-04: Systematic reconstruction of regulatory networks in mammalian cells: Lessons from the pathogen response

Abstract

Abstract Deciphering the regulatory networks that control dynamic and specific gene expression responses in mammalian cells remains a major challenge. While models inferred from genomic data have identified candidate regulatory mechanisms, such models remain largely unvalidated. Here, we present an unbiased strategy based on systematic gene perturbation and innovative multiplex detection to derive regulatory networks in mammalian cells. We apply this approach to decipher the network that controls the transcriptional response to pathogens in primary dendritic cells (DCs), testing the regulatory function of 125 transcription factors, chromatin modifiers, and RNA binding proteins. Our approach accurately assigned 32 known regulators (e.g. NFκB, IRFs, and STATs) to their target genes and discovered 68 additional functional regulators that were not previously implicated in this response. We quantify the contribution of each regulator to two major transcriptional programs (inflammatory and antiviral), identifying a core network of two dozen key regulators and 76 fine-tuners, that uses a combination of coherent feed-forward circuits, dominant activation, and cross-inhibition to control response specificity. Among these we discover a tier of chromatin modifiers that specifically repress interferon beta 1 (IFNβ1) expression upon bacterial but not viral stimulation, and a large circuit of cell cycle regulators that was co-opted to regulate the viral response. Our work establishes a broadly-applicable, comprehensive and unbiased approach to identifying the wiring and function of a regulatory network controlling a major transcriptional response in primary mammalian cells. Citation Format: Aviv Regev. Systematic reconstruction of regulatory networks in mammalian cells: Lessons from the pathogen response [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY15-04