Altered regulation and expression of genes by BET family of proteins in COPD patients

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http://hdl.handle.net/10138/178656

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Malhotra , R , Kurian , N , Zhou , X-H , Jiang , F , Monkley , S , DeMicco , A , Clausen , I G , Dellgren , G , Edenro , G , Ahdesmaki , M J , Clausen , M , Oberg , L , Israelsson , E , Belfield , G & Vaarala , O 2017 , ' Altered regulation and expression of genes by BET family of proteins in COPD patients ' , PLoS One , vol. 12 , no. 3 , 0173115 . https://doi.org/10.1371/journal.pone.0173115

Title: Altered regulation and expression of genes by BET family of proteins in COPD patients
Author: Malhotra, Rajneesh; Kurian, Nisha; Zhou, Xiao-Hong; Jiang, Fanyi; Monkley, Susan; DeMicco, Amy; Clausen, Ib G.; Dellgren, Göran; Edenro, Goran; Ahdesmaki, Miika J.; Clausen, Maryam; Oberg, Lisa; Israelsson, Elisabeth; Belfield, Graham; Vaarala, Outi
Contributor organization: Clinicum
HUS Children and Adolescents
Date: 2017-03-01
Language: eng
Number of pages: 17
Belongs to series: PLoS One
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0173115
URI: http://hdl.handle.net/10138/178656
Abstract: Background BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co-regulators. BET proteins bind to acetylated lysine residues in the histones of nucleosomal chromatin and function either as co-activators or co-repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that pan-BET inhibitor (JQ1) treatment of BET protein interactions with hyperacety-lated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD. Methods and findings Transcriptome analysis of AM from COPD patients indicated up-regulation of macrophage M1 type genes upon LPS stimulation. Pan-BET inhibitor JQ1 treatment attenuated expression of multiple genes, including pro-inflammatory cytokines and regulators of innate and adaptive immune cells. We demonstrated for the first time that JQ1 differentially modulated LPS-induced cytokine release from AM or peripheral blood mononuclear cells (PBMC) of COPD patients compared to PBMC of healthy controls. Using the BET regulated gene signature, we identified a subset of COPD patients, which we propose to benefit from BET inhibition. Conclusions This work demonstrates that the effects of pan-BET inhibition through JQ1 treatment of inflammatory cells differs between COPD patients and healthy controls, and the expression of BET protein regulated genes is altered in COPD. These findings provide evidence of histone hyperacetylation as a mechanism driving chronic inflammatory changes in COPD.
Description: Correction: PLoS One 2018 12 (4): 0175997
Subject: OBSTRUCTIVE PULMONARY-DISEASE
BROMODOMAIN INHIBITION
CIGARETTE-SMOKE
LIPOPOLYSACCHARIDE
RESPONSES
GENETICS
REVEALS
CELLS
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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