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Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.

IIott NE, Heward JA, Roux B, Tsitsiou E, Fenwick PS, Lenzi L, Goodhead I, Hertz-Fowler C, Heger A, Hall N, Donnelly LE, Sims D, Lindsay MA - Nat Commun (2014)

Bottom Line: Early reports indicate that long non-coding RNAs (lncRNAs) are novel regulators of biological responses.Crucially, we demonstrate that knockdown of nuclear-localized, NF-κB-regulated, eRNAs (IL1β-eRNA) and RBT (IL1β-RBT46) surrounding the IL1β locus, attenuates LPS-induced messenger RNA transcription and release of the proinflammatory mediators, IL1β and CXCL8.We predict that lncRNAs can be important regulators of the human innate immune response.

View Article: PubMed Central - PubMed

Affiliation: 1] CGAT Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK [2].

ABSTRACT
Early reports indicate that long non-coding RNAs (lncRNAs) are novel regulators of biological responses. However, their role in the human innate immune response, which provides the initial defence against infection, is largely unexplored. To address this issue, here we characterize the long non-coding RNA transcriptome in primary human monocytes using RNA sequencing. We identify 76 enhancer RNAs (eRNAs), 40 canonical lncRNAs, 65 antisense lncRNAs and 35 regions of bidirectional transcription (RBT) that are differentially expressed in response to bacterial lipopolysaccharide (LPS). Crucially, we demonstrate that knockdown of nuclear-localized, NF-κB-regulated, eRNAs (IL1β-eRNA) and RBT (IL1β-RBT46) surrounding the IL1β locus, attenuates LPS-induced messenger RNA transcription and release of the proinflammatory mediators, IL1β and CXCL8. We predict that lncRNAs can be important regulators of the human innate immune response.

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eRNA expression correlates with protein-coding gene expression.(a) Distribution of distances from the closest expressed protein-coding gene for eRNAs and can-lncRNAs. (b) Correlation between absolute fold changes for eRNAs and can-lncRNAs with their nearest expressed protein-coding gene neighbour.
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f3: eRNA expression correlates with protein-coding gene expression.(a) Distribution of distances from the closest expressed protein-coding gene for eRNAs and can-lncRNAs. (b) Correlation between absolute fold changes for eRNAs and can-lncRNAs with their nearest expressed protein-coding gene neighbour.

Mentions: Transcription from enhancers has been linked with the activity of nearby protein-coding loci. To investigate whether monocytic eRNAs were regulated alongside protein-coding genes, we assessed the correlation of fold changes between eRNAs and can-lncRNAs with their closest expressed protein-coding gene neighbours. Although our eRNAs were no closer in proximity to protein-coding genes than can-lncRNAs (Fig. 3a), the correlation in fold change (LPS-stimulated versus unstimulated) between eRNAs and their closest protein-coding gene neighbour was stronger than that of can-lncRNAs (Fig. 3b, r=0.52 and 0.24, respectively). Of particular interest were eRNAs paired with protein-coding genes known to have roles in the monocytic inflammatory response. Such genes included PTGS2, IRF2 (Fig. 3b), ACSL1, MARCKS, IL6 (Fig. 3b), IL10RA, IL10RB and interleukin 1β (IL1β) (Fig. 3b) (see Supplementary Table 4 online).


Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.

IIott NE, Heward JA, Roux B, Tsitsiou E, Fenwick PS, Lenzi L, Goodhead I, Hertz-Fowler C, Heger A, Hall N, Donnelly LE, Sims D, Lindsay MA - Nat Commun (2014)

eRNA expression correlates with protein-coding gene expression.(a) Distribution of distances from the closest expressed protein-coding gene for eRNAs and can-lncRNAs. (b) Correlation between absolute fold changes for eRNAs and can-lncRNAs with their nearest expressed protein-coding gene neighbour.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061460&req=5

f3: eRNA expression correlates with protein-coding gene expression.(a) Distribution of distances from the closest expressed protein-coding gene for eRNAs and can-lncRNAs. (b) Correlation between absolute fold changes for eRNAs and can-lncRNAs with their nearest expressed protein-coding gene neighbour.
Mentions: Transcription from enhancers has been linked with the activity of nearby protein-coding loci. To investigate whether monocytic eRNAs were regulated alongside protein-coding genes, we assessed the correlation of fold changes between eRNAs and can-lncRNAs with their closest expressed protein-coding gene neighbours. Although our eRNAs were no closer in proximity to protein-coding genes than can-lncRNAs (Fig. 3a), the correlation in fold change (LPS-stimulated versus unstimulated) between eRNAs and their closest protein-coding gene neighbour was stronger than that of can-lncRNAs (Fig. 3b, r=0.52 and 0.24, respectively). Of particular interest were eRNAs paired with protein-coding genes known to have roles in the monocytic inflammatory response. Such genes included PTGS2, IRF2 (Fig. 3b), ACSL1, MARCKS, IL6 (Fig. 3b), IL10RA, IL10RB and interleukin 1β (IL1β) (Fig. 3b) (see Supplementary Table 4 online).

Bottom Line: Early reports indicate that long non-coding RNAs (lncRNAs) are novel regulators of biological responses.Crucially, we demonstrate that knockdown of nuclear-localized, NF-κB-regulated, eRNAs (IL1β-eRNA) and RBT (IL1β-RBT46) surrounding the IL1β locus, attenuates LPS-induced messenger RNA transcription and release of the proinflammatory mediators, IL1β and CXCL8.We predict that lncRNAs can be important regulators of the human innate immune response.

View Article: PubMed Central - PubMed

Affiliation: 1] CGAT Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK [2].

ABSTRACT
Early reports indicate that long non-coding RNAs (lncRNAs) are novel regulators of biological responses. However, their role in the human innate immune response, which provides the initial defence against infection, is largely unexplored. To address this issue, here we characterize the long non-coding RNA transcriptome in primary human monocytes using RNA sequencing. We identify 76 enhancer RNAs (eRNAs), 40 canonical lncRNAs, 65 antisense lncRNAs and 35 regions of bidirectional transcription (RBT) that are differentially expressed in response to bacterial lipopolysaccharide (LPS). Crucially, we demonstrate that knockdown of nuclear-localized, NF-κB-regulated, eRNAs (IL1β-eRNA) and RBT (IL1β-RBT46) surrounding the IL1β locus, attenuates LPS-induced messenger RNA transcription and release of the proinflammatory mediators, IL1β and CXCL8. We predict that lncRNAs can be important regulators of the human innate immune response.

Show MeSH
Related in: MedlinePlus