Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease

J. Kenneth Baillie, Erik Arner, Carsten O. Daub, Michiel J L De Hoon, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Alistair R. R. Forrest, Yoshihide Hayashizaki, Fantom Consortium, Geoffrey J. Faulkner, Christine A. Wells, Michael Rehli, Paul Pavli, Kim M. Summers, David A. Hume

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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.

Original languageEnglish
Article number1006641
Number of pages36
JournalPLoS Genetics
Volume13
Issue number3
DOIs
Publication statusPublished - 6 Mar 2017
Externally publishedYes

Cite this

Baillie, J. Kenneth ; Arner, Erik ; Daub, Carsten O. ; De Hoon, Michiel J L ; Itoh, Masayoshi ; Kawaji, Hideya ; Lassmann, Timo ; Carninci, Piero ; Forrest, Alistair R. R. ; Hayashizaki, Yoshihide ; Consortium, Fantom ; Faulkner, Geoffrey J. ; Wells, Christine A. ; Rehli, Michael ; Pavli, Paul ; Summers, Kim M. ; Hume, David A. / Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease. In: PLoS Genetics. 2017 ; Vol. 13, No. 3.
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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.",
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Baillie, JK, Arner, E, Daub, CO, De Hoon, MJL, Itoh, M, Kawaji, H, Lassmann, T, Carninci, P, Forrest, ARR, Hayashizaki, Y, Consortium, F, Faulkner, GJ, Wells, CA, Rehli, M, Pavli, P, Summers, KM & Hume, DA 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, vol. 13, no. 3, 1006641. https://doi.org/10.1371/journal.pgen.1006641

Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease. / Baillie, J. Kenneth; Arner, Erik; Daub, Carsten O.; De Hoon, Michiel J L; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Carninci, Piero; Forrest, Alistair R. R.; Hayashizaki, Yoshihide; Consortium, Fantom; Faulkner, Geoffrey J.; Wells, Christine A.; Rehli, Michael; Pavli, Paul; Summers, Kim M.; Hume, David A.

In: PLoS Genetics, Vol. 13, No. 3, 1006641, 06.03.2017.

Research output: Contribution to journalArticle

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AU - Baillie, J. Kenneth

AU - Arner, Erik

AU - Daub, Carsten O.

AU - De Hoon, Michiel J L

AU - Itoh, Masayoshi

AU - Kawaji, Hideya

AU - Lassmann, Timo

AU - Carninci, Piero

AU - Forrest, Alistair R. R.

AU - Hayashizaki, Yoshihide

AU - Consortium, Fantom

AU - Faulkner, Geoffrey J.

AU - Wells, Christine A.

AU - Rehli, Michael

AU - Pavli, Paul

AU - Summers, Kim M.

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KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - GENOME-WIDE ASSOCIATION

KW - STIMULATING FACTOR-I

KW - CROHNS-DISEASE

KW - INTESTINAL HOMEOSTASIS

KW - NEGATIVE REGULATOR

KW - FUNCTIONAL VARIANTS

KW - SUSCEPTIBILITY LOCI

KW - MEDIATED ACTIVATION

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SN - 1553-7390

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