Mechanisms establishing tlr4-responsive activation states of inflammatory response genes

Laure Escoubet-Lozach, Christopher Benner, Minna U. Kaikkonen, Jean Lozach, Sven Heinz, Nathan J. Spann, Andrea Crotti, Josh Stender, Serena Ghisletti, Donna Reichart, Christine S. Cheng, Rosa Luna, Colleen Ludka, Roman Sasik, Ivan Garcia-Bassets, Alexander Hoffmann, Shankar Subramaniam, Gary Hardiman, Michael G. Rosenfeld, Christopher K. Glass

Research output: Contribution to journalArticlepeer-review

Abstract

Precise control of the innate immune response is required for resistance to microbial infections and maintenance of normal tissue homeostasis. Because this response involves coordinate regulation of hundreds of genes, it provides a powerful biological system to elucidate the molecular strategies that underlie signal- and time-dependent transitions of gene expression. Comprehensive genome-wide analysis of the epigenetic and transcription status of the TLR4-induced transcriptional program in macrophages suggests that Toll-like receptor 4 (TLR4)-dependent activation of nearly all immediate/early- (I/E) and late-response genes results from a sequential process in which signal-independent factors initially establish basal levels of gene expression that are then amplified by signal-dependent transcription factors. Promoters of I/E genes are distinguished from those of late genes by encoding a distinct set of signal-dependent transcription factor elements, including TATA boxes, which lead to preferential binding of TBP and basal enrichment for RNA polymerase II immediately downstream of transcriptional start sites. Global nuclear run-on (GRO) sequencing and total RNA sequencing further indicates that TLR4 signaling markedly increases the overall rates of both transcriptional initiation and the efficiency of transcriptional elongation of nearly all I/E genes, while RNA splicing is largely unaffected. Collectively, these findings reveal broadly utilized mechanisms underlying temporally distinct patterns of TLR4-dependent gene activation required for homeostasis and effective immune responses.

Original languageEnglish
Article numbere1002401
JournalPLoS Genetics
Volume7
Issue number12
DOIs
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

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