Gene expression networks in COPD: microRNA and mRNA regulation

Ezzie, Michael E.; Crawford, Melissa; Cho, Ji-Hoon; Orellana, Robert C; Zhang, Shile; Gelinas, Richard; Batte, Kara; Yu, Lianbo; Nuovo, Gerard J.; Galas, David J.; Diaz, Philip T.; Wang, Kai; Nana‐Sinkam, S. Patrick

doi:10.1136/thoraxjnl-2011-200089

Cited by 300 publications

(301 citation statements)

References 40 publications

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“…In stimulation experiments using endothelial cells that, in vivo, reflect the first responders of the lungs to these proinflammatory signals, we found that IL-1β and TNFα significantly induced the levels of miR-223 in a time-dependent manner. These cytokines have been described as key inflammatory mediators in COPD [2,3] and their activity in COPD patients might explain the significant upregulation of miR-223 levels in vivo as shown by Ezzie and colleagues [21]. Both cytokines are activators of the transcription factor nuclear factor kappa B (NF-κB).…”

Section: Discussionmentioning

confidence: 96%

“…miRNAs have emerged as post-transcriptional gene silencers and we thus suggested their involvement in the decreased expression of HDAC2. In the context of COPD, miR-223 was recently described as the most upregulated miRNA in lung tissue of patients but its function has not been addressed [21]. Several miRNA target prediction algorithms identified potential binding sites of miRNAs that included seed matches for miR-223 in the 3'UTR of HDAC2 [18].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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 miRNAtarget 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-1 and tumor necrosis factor-. 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. AbstractReduced 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 i...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…RCR was performed using Gene Expression Omnibus (GEO) COPD and emphysema data sets from lung, small airway, and alveolar macrophages of early COPD patients and healthy smokers (see Dataset) 59– 63 . RCR has been used previously to predict upstream regulators from transcriptomic data 8 .…”

Section: Methodsmentioning

confidence: 99%

Enhancement of COPD biological networks using a web-based collaboration interface

et al. 2015

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The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest stage. COPD network models are important tools to better understand the biological components and processes underlying initial disease development. With the increasing amounts of literature that are now available, crowdsourcing approaches offer new forms of collaboration for researchers to review biological findings, which can be applied to the construction and verification of complex biological networks. We report the construction of 50 biological network models relevant to lung biology and early COPD using an integrative systems biology and collaborative crowd-verification approach. By combining traditional literature curation with a data-driven approach that predicts molecular activities from transcriptomics data, we constructed an initial COPD network model set based on a previously published non-diseased lung-relevant model set. The crowd was given the opportunity to enhance and refine the networks on a website ( https://bionet.sbvimprover.com/) and to add mechanistic detail, as well as critically review existing evidence and evidence added by other users, so as to enhance the accuracy of the biological representation of the processes captured in the networks. Finally, scientists and experts in the field discussed and refined the networks during an in-person jamboree meeting. Here, we describe examples of the changes made to three of these networks: Neutrophil Signaling, Macrophage Signaling, and Th1-Th2 Signaling. We describe an innovative approach to biological network construction that combines literature and data mining and a crowdsourcing approach to generate a comprehensive set of COPD-relevant models that can be used to help understand the mechanisms related to lung pathobiology. Registered users of the website can freely browse and download the networks.

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“…Expression profiling of lung tissue from subjects with COPD and smokers without COPD has revealed 70 miRNAs that are differentially expressed, including miR-223, miR-127a, miR-424 and miR-15b [115]. The group concentrated on miR-15b and found that expression correlated with severity of COPD as assessed by spirometry [115].…”

Section: B-cellsmentioning

confidence: 99%

“…The group concentrated on miR-15b and found that expression correlated with severity of COPD as assessed by spirometry [115]. Interestingly, miR-15b was able to regulate components of the transforming growth factor (TGF)-b pathway, a key growth factor implicated in airway remodelling in COPD.…”

Section: B-cellsmentioning

confidence: 99%

MicroRNAs and respiratory diseases

2012

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MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that modulate physiological and pathological processes by post-transcriptional inhibition of gene expression. They were first recognised as regulators of development in worms and fruitflies. In recent years extensive research has explored their pivotal role in the pathogenesis of human diseases. Over 1,000 human miRNAs have been discovered to date; however, the biological function and protein targets for the majority remain to be uncovered. Within the respiratory system, miRNAs are important in normal pulmonary development and maintaining lung homeostasis. Recent studies have also begun to reveal that altered miRNA expression profiles may be associated with pathological processes within the lung and lead to the development of various pulmonary diseases, ranging from inflammatory diseases to lung cancers. Advancing our understanding of the role of miRNAs in the respiratory system will help provide new perspectives on disease mechanisms and reveal intriguing therapeutic targets and diagnostic markers for respiratory disorders.

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Gene expression networks in COPD: microRNA and mRNA regulation

Cited by 300 publications

References 40 publications

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

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

Enhancement of COPD biological networks using a web-based collaboration interface

MicroRNAs and respiratory diseases

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