title: Mechanisms establishing TLR4-responsive activation states of inflammatory response genes.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Laure
authors.initials: L
authors.lastname: Escoubet-Lozach
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: Jean
authors.initials: J
authors.lastname: Lozach
authors.forename: Sven
authors.initials: S
authors.lastname: Heinz
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Spann
authors.forename: Andrea
authors.initials: A
authors.lastname: Crotti
authors.forename: Josh
authors.initials: J
authors.lastname: Stender
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.forename: Donna
authors.initials: D
authors.lastname: Reichart
authors.forename: Christine S
authors.initials: CS
authors.lastname: Cheng
authors.forename: Rosa
authors.initials: R
authors.lastname: Luna
authors.forename: Colleen
authors.initials: C
authors.lastname: Ludka
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.forename: Ivan
authors.initials: I
authors.lastname: Garcia-Bassets
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016385:TATA Box / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
chemical_list: D006657:Histones; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II