title: Dual transcriptome sequencing reveals resistance of TLR4 ligand-activated bone marrow-derived macrophages to inflammation mediated by the BET inhibitor JQ1.
abstract: Persistent macrophage activation is associated with the expression of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify inflammatory disorders. A novel synthetic BET inhibitor, JQ1, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for JQ1 molecular targets has not been undertaken. The present study aimed at evaluating the anti-inflammatory function and underlying genes that are targeted by JQ1 in LPS-stimulated primary bone marrow-derived macrophages (BMDMs) using global transcriptomic RNA sequencing and quantitative real-time PCR. Among the annotated genes, transcriptional sequencing of BMDMs that were treated with JQ1 revealed a selective effect on LPS-induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs was suppressed. Additionally, we found that JQ1 reduced the expression of previously unidentified genes that are important in inflammation. Importantly, these inflammatory genes were not affected by JQ1 treatment alone. Furthermore, we confirmed that JQ1 reduced cytokines/chemokines in the supernatants of LPS treated BMDMs. Moreover, the biological pathways and gene ontology of the differentially expressed genes were determined in the JQ1 treatment of BMDMs. These unprecedented results suggest that the BET inhibitor JQ1 is a candidate for the prevention or therapeutic treatment of inflammatory disorders.
authors.affiliation: Department of Bionanotechnology, Hanyang University, Seoul, 133-791, Republic of Korea.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Molecular &Life Sciences, Hanyang University, Ansan, 426-791, Republic of Korea.
authors.forename: Jin Choul
authors.initials: JC
authors.lastname: Chai
authors.affiliation: Department of Molecular &Life Sciences, Hanyang University, Ansan, 426-791, Republic of Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Department of Molecular &Life Sciences, Hanyang University, Ansan, 426-791, Republic of Korea.
authors.forename: Young Seek
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Epigenetics Drug Discovery Unit, Division of Structural &Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Yokohama 230-0045, Japan.
authors.forename: Nando Dulal
authors.initials: ND
authors.lastname: Das
authors.affiliation: Institute of Natural Science &Technology, Hanyang University, Ansan, 426-791, Republic of Korea.
authors.forename: Kyoung Hwa
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Bionanotechnology, Hanyang University, Seoul, 133-791, Republic of Korea.|Department of Molecular &Life Sciences, Hanyang University, Ansan, 426-791, Republic of Korea.
authors.forename: Young Gyu
authors.initials: YG
authors.lastname: Chai
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000473:pathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000473:pathology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D058977:Molecular Sequence Annotation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D008024:Ligands; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014230:Triazoles