title: Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease.
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 colony-stimulating 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 non-coding 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. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease.
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
authors.forename: J Kenneth
authors.identifier: 0000-0001-5258-793X
authors.initials: JK
authors.lastname: Baillie
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Arner
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Carsten
authors.identifier: 0000-0002-3295-8729
authors.initials: C
authors.lastname: Daub
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Michiel
authors.initials: M
authors.lastname: De Hoon
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Masayoshi
authors.identifier: 0000-0002-1772-318X
authors.initials: M
authors.lastname: Itoh
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Hideya
authors.identifier: 0000-0002-0575-0308
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Timo
authors.identifier: 0000-0002-0138-2691
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Alistair R R
authors.identifier: 0000-0003-4543-1675
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
authors.forename: Geoffrey J
authors.identifier: 0000-0001-5769-4494
authors.initials: GJ
authors.lastname: Faulkner
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, Brisbane St Lucia, Queensland, Australia.
authors.forename: Christine A
authors.identifier: 0000-0003-3133-3628
authors.initials: CA
authors.lastname: Wells
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, F.-J.-Strauss Allee 11, Regensburg, Germany.
authors.forename: Michael
authors.identifier: 0000-0003-3992-932X
authors.initials: M
authors.lastname: Rehli
authors.affiliation: Medical School, Australian National University, Canberra, ACT, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Pavli
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Summers
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
mesh_terms: D020816:Amino Acid Motifs; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology*; D009000:Monocytes / Q000166:cytology*; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D014157:Transcription Factors; D016173:Macrophage Colony-Stimulating Factor