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RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

dc.contributor.author Zhang, Xiaoling
dc.contributor.author Jin, Jane Y
dc.contributor.author Wu, Joseph
dc.contributor.author Qin, Xiaoxia
dc.contributor.author Streilein, Robert
dc.contributor.author Hall, Russell P
dc.contributor.author Zhang, Jennifer Y
dc.coverage.spatial United States
dc.date.accessioned 2017-08-02T13:58:40Z
dc.date.available 2017-08-02T13:58:40Z
dc.date.issued 2015-04
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/25501661
dc.identifier S0022-202X(15)37204-3
dc.identifier.uri https://hdl.handle.net/10161/15166
dc.description.abstract Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.
dc.language eng
dc.publisher Nature Publishing Group
dc.relation.ispartof J Invest Dermatol
dc.relation.isversionof 10.1038/jid.2014.519
dc.subject Adaptor Proteins, Signal Transducing
dc.subject Animals
dc.subject Cell Adhesion
dc.subject Cell Proliferation
dc.subject Chemokine CCL2
dc.subject Chemokine CXCL10
dc.subject Chromatin Immunoprecipitation
dc.subject Cytokines
dc.subject Epidermis
dc.subject Gene Deletion
dc.subject Genes, Reporter
dc.subject HEK293 Cells
dc.subject Heat-Shock Proteins
dc.subject Humans
dc.subject Inflammation
dc.subject Keratinocytes
dc.subject Mice
dc.subject Mutation
dc.subject NF-kappa B
dc.subject Oligonucleotide Array Sequence Analysis
dc.subject Pyrrolidines
dc.subject Regeneration
dc.subject Sequence Analysis, RNA
dc.subject Sequestosome-1 Protein
dc.subject Skin Physiological Phenomena
dc.subject Thiocarbamates
dc.subject Transcription Factors
dc.title RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.
dc.type Journal article
duke.contributor.id Hall, Russell P|0117605
duke.contributor.id Zhang, Jennifer Y|0380897
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/25501661
pubs.begin-page 1016
pubs.end-page 1024
pubs.issue 4
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Dermatology
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Immunology
pubs.organisational-group Institutes and Centers
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 135
dc.identifier.eissn 1523-1747
duke.contributor.orcid Hall, Russell P|0000-0001-7621-4935
duke.contributor.orcid Zhang, Jennifer Y|0000-0002-4485-1750


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