title: Altered regulation and expression of genes by BET family of proteins in 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 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 hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Rajneesh
authors.initials: R
authors.lastname: Malhotra
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Nisha
authors.initials: N
authors.lastname: Kurian
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhou
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Fanyi
authors.initials: F
authors.lastname: Jiang
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Susan
authors.initials: S
authors.lastname: Monkley
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Amy
authors.initials: A
authors.lastname: DeMicco
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Ib G
authors.initials: IG
authors.lastname: Clausen
authors.forename: Göran
authors.lastname: Dellgren
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Goran
authors.initials: G
authors.lastname: Edenro
authors.affiliation: AstraZeneca, Oncology iMed, AstraZeneca, Cambridge, CB2 0RE, United Kingdom.
authors.forename: Miika J
authors.initials: MJ
authors.lastname: Ahdesmäki
authors.affiliation: AstraZeneca, Discovery Sciences, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Maryam
authors.initials: M
authors.lastname: Clausen
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Öberg
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Israelsson
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.
authors.forename: Graham
authors.initials: G
authors.lastname: Belfield
authors.affiliation: AstraZeneca, Respiratory, Inflammation and Autoimmunity iMed, Pepparedsleden 1, Mölndal, Sweden.|Clinicum, University of Helsinki, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
mesh_terms: D001381:Azepines / Q000494:pharmacology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D016207:Cytokines; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C109570:BRDT protein, human