Genomics

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


ABSTRACT: 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 lysines 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 BET inhibitor (JQ1) treatment of BET protein interactions with hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes and survival of key inflammatory drivers, alveolar macrophages (AM) in COPD. Transcriptome analysis of AM from COPD patients indicated up-regulation of macrophage type 1 genes upon LPS stimulation. BET inhibitor JQ1 treatment attenuated expression of multiple genes, including pro-inflammatory cytokines and regulators innate and adaptive immune cells. We demonstrated for the first time that JQ1 regulates differentially LPS-induced cytokine release from AM or peripheral blood mononuclear cells (PBMC) of COPD patients than PBMC of healthy controls. Using BET regulated gene signature, we identified a subset of COPD patients, which we propose to benefit from BET inhibition. This work demonstrates that the effects of BET inhibition through JQ1 treatment of inflammatory cells has the potential to restore gene expression dysregulated in COPD patients vs healthy controls, and the expression of BET regulated genes is altered in COPD. The findings provide evidence of histone hyperacetylation as a mechanism driving chronic inflammatory changes in COPD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE92532 | GEO | 2017/03/02

SECONDARY ACCESSION(S): PRJNA357923

REPOSITORIES: GEO

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