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MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD


Leuenberger, Caroline; Schuoler, Claudio; Bye, Hannah; Mignan, Célia; Rechsteiner, Thomas; Hillinger, Sven; Opitz, Isabelle; Marsland, Benjamin; Faiz, Alen; Hiemstra, Pieter S; Timens, Wim; Camici, Giovanni G; Kohler, Malcolm; Huber, Lars C; Brock, Matthias (2016). MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD. Journal of Molecular Medicine, 94(6):725-734.

Abstract

Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNA-target interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD.
KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1β and tumor necrosis factor-α. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients.

Abstract

Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNA-target interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD.
KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1β and tumor necrosis factor-α. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Pneumology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:11 February 2016
Deposited On:09 Mar 2016 13:58
Last Modified:11 Feb 2017 01:00
Publisher:Springer
ISSN:0946-2716
Publisher DOI:https://doi.org/10.1007/s00109-016-1388-1
PubMed ID:26864305

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