Baillie, J. Kenneth and Arner, Erik and Daub, Carsten and De Hoon, Michiel and Itoh, Masayoshi and Kawaji, Hideya and Lassmann, Timo and Carninci, Piero and Forrest, Alistair R. R. and Hayashizaki, Yoshihide and Consortium, Fantom and Faulkner, Geoffrey J. and Wells, Christine A. and Rehli, Michael and Pavli, Paul and Summers, Kim M. and Hume, David A. (2017) Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease. PLOS GENETICS, 13 (3): e1006641. ISSN 1553-7404,
Full text not available from this repository. (Request a copy)Abstract
The FANTOM5 consortium utilised cap analysis of gene expression ( CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte- derived macrophages grown in macrophage colonystimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS- inducible long noncoding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte- macrophage transitions and/or in response to LPS.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; STIMULATING FACTOR-I; CROHNS-DISEASE; INTESTINAL HOMEOSTASIS; NEGATIVE REGULATOR; FUNCTIONAL VARIANTS; SUSCEPTIBILITY LOCI; MEDIATED ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:00 |
| Last Modified: | 26 Feb 2019 09:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/254 |
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