Dataset Information

Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells.

ABSTRACT: Transcription factors play a key role in integrating and modulating biological information. In this study, we comprehensively measured the changing abundances of mRNAs over a time course of activation of human peripheral-blood-derived mononuclear cells ("macrophages") with lipopolysaccharide. Global and dynamic analysis of transcription factors in response to a physiological stimulus has yet to be achieved in a human system, and our efforts significantly advanced this goal. We used multiple global high-throughput technologies for measuring mRNA levels, including massively parallel signature sequencing and GeneChip microarrays. We identified 92 of 1,288 known human transcription factors as having significantly measurable changes during our 24-h time course. At least 42 of these changes were previously unidentified in this system. Our data demonstrate that some transcription factors operate in a functional range below 10 transcripts per cell, whereas others operate in a range three orders of magnitude greater. The highly reproducible response of many mRNAs indicates feedback control. A broad range of activation kinetics was observed; thus, combinatorial regulation by small subsets of transcription factors would permit almost any timing input to cis-regulatory elements controlling gene transcription.

SUBMITTER: Roach JC

PROVIDER: S-EPMC2042192 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells.

Roach Jared C JC Smith Kelly D KD Strobe Katie L KL Nissen Stephanie M SM Haudenschild Christian D CD Zhou Daixing D Vasicek Thomas J TJ Held G A GA Stolovitzky Gustavo A GA Hood Leroy E LE Aderem Alan A

Proceedings of the National Academy of Sciences of the United States of America 20071003 41

Transcription factors play a key role in integrating and modulating biological information. In this study, we comprehensively measured the changing abundances of mRNAs over a time course of activation of human peripheral-blood-derived mononuclear cells ("macrophages") with lipopolysaccharide. Global and dynamic analysis of transcription factors in response to a physiological stimulus has yet to be achieved in a human system, and our efforts significantly advanced this goal. We used multiple glob ...[more]

PMID: 17913878

Similar Datasets

Project description:BackgroundThe monkey is a primary species used in toxicological research. However, the failures of preclinical studies to predict a life-threatening "cytokine storm", which, for instance, rapidly occurred in six healthy volunteers with the CD28 superagonist monoclonal antibody (mAb) TGN1412 in the first-in-human phase I clinical trial, have emphasized a need to clarify the differences between human and monkey immune systems.MethodsIn the present study, we analyzed and compared the lymphocyte proliferation, cytokine secretion, and gene expression profiles after phytohemagglutinin (PHA) and lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) from three healthy humans and cynomolgus monkeys (Macaca fascicularis).ResultsThe results derived from comparison with the corresponding control groups showed that PHA in humans induced a stronger proliferation and wider range of cytokine secretion, along with a greater number of differently expressed genes (DEGs), than when PHA was applied in cynomolgus monkeys. The significant upregulation of genes involved in the mitotic cell cycle, including cyclin B2, TOP2A, TYMS, and CEP55, was observed in human PBMCs with PHA stimulation, while only infrequent or slight upregulation occurred in cynomolgus monkey PBMCs, which may be one of the reasons for a stronger response to PHA in humans. In contrast to PHA, LPS in both species induced a similar proliferation ratio, cytokine profile, and DEG count, suggesting that human and cynomolgus monkeys have a similar response intensity for innate immune responses. Furthermore, 38 and 20 overlapped genes under PHA and LPS stimulation, respectively, were found in both species. These overlapped DEGs were associated with the same biological functions, including DNA replication, mitosis, immune response, chemotaxis, and inflammatory response. Thus, these results might reflect the highly conserved signatures of immune responses to PHA/LPS stimulation across the primates. Moreover, there were some differences in antigen processing and presentation, and the interferon gamma (INF-γ)-mediated signaling pathway in these species detected by gene expression profile study.ConclusionsIn conclusion, this is the first study to compare data on the responses of PBMCs to PHA and LPS in humans versus cynomolgus monkeys, and these findings may provide crucial insights into translating non-human primate (NHP) studies into human trials.

Project description:The innate immune response to lipopolysaccharide contributes substantially to the morbidity and mortality of gram-negative sepsis. Horses and humans share an exquisite sensitivity to lipopolysaccharide and thus the horse may provide valuable comparative insights into this aspect of the inflammatory response. MicroRNAs, small non-coding RNA molecules acting as post-transcriptional regulators of gene expression, have key roles in toll-like receptor signaling regulation but have not been studied in this context in horses. The central hypothesis of this study was that lipopolysaccharide induces differential microRNA expression in equine peripheral blood mononuclear cells in a manner comparable to humans. Illumina Next Generation Sequencing was used to characterize the basal microRNA transcriptome in isolated peripheral blood mononuclear cells from healthy adult horses, and to evaluate LPS-induced changes in microRNA expression in cells cultured for up to four hours. Selected expression changes were validated using quantitative reverse-transcriptase PCR. Only miR-155 was significantly upregulated by LPS, changing in parallel with supernatant tumor necrosis factor-? concentration. Eight additional microRNAs, including miR-146a and miR-146b, showed significant expression change with time in culture without a clear LPS effect. Target predictions indicated a number of potential immunity-associated targets for miR-155 in the horse, including SOCS1, TAB2 and elements of the PI3K signaling pathway, suggesting that it is likely to influence the acute inflammatory response to LPS. Gene alignment showed extensive conservation of the miR-155 precursor gene and associated promoter regions between horses and humans. The basal and LPS-stimulated microRNA expression pattern characterized here were similar to those described in human leukocytes. As well as providing a resource for further research into the roles of microRNAs in immune responses in horses, this will facilitate inter-species comparative study of the role of microRNAs in the inflammatory cascade during endotoxemia and sepsis.

Project description:BackgroundAltered expression of transcription factor specificity protein 4 (SP4) has been found in the postmortem brain of patients with psychiatric disorders including schizophrenia and bipolar disorder. Reduced levels of SP4 protein have recently been reported in peripheral blood mononuclear cells in first-episode psychosis. Also, SP4 levels are modulated by lithium treatment in cultured neurons. Phosphorylation of SP4 at S770 is increased in the cerebellum of bipolar disorder subjects and upon inhibition of NMDA receptor signaling in cultured neurons. The aim of this study was to investigate whether SP4 S770 phosphorylation is increased in lymphocytes of first-episode psychosis patients and the effect of lithium treatment on this phosphorylation.MethodsA cross-sectional study of S770 phosphorylation relative to total SP4 immunoreactivity using specific antibodies in peripheral blood mononuclear cells in first-episode psychosis patients (n = 14, treated with lithium or not) and matched healthy controls (n = 14) by immunoblot was designed. We also determined the effects of the prescribed drugs lithium, olanzapine or valproic acid on SP4 phosphorylation in rat primary cultured cerebellar granule neurons.ResultsWe found that SP4 S770 phosphorylation was significantly increased in lymphocytes in first-episode psychosis compared to controls and decreased in patients treated with lithium compared to patients who did not receive lithium. Moreover, incubation with lithium but not olanzapine or valproic acid reduced SP4 phosphorylation in rat cultured cerebellar granule neurons.ConclusionsThe findings presented here indicate that SP4 S770 phosphorylation is increased in lymphocytes in first-episode psychosis which may be reduced by lithium treatment in patients. Moreover, our study shows lithium treatment prevents this phosphorylation in vitro in neurons. This pilot study suggests that S770 SP4 phosphorylation could be a peripheral biomarker of psychosis, and may be regulated by lithium treatment in first-episode psychosis.

Dataset Information

Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells.

Publications

Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets