title: Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells.
abstract: STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich., USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Matthew
authors.initials: M
authors.lastname: Iyer
authors.forename: Richard
authors.initials: R
authors.lastname: McEachin
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.forename: Yi-Mi
authors.initials: YM
authors.lastname: Wu
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Katherine
authors.initials: K
authors.lastname: Oravecz-Wilson
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zajac
authors.forename: Nathan
authors.initials: N
authors.lastname: Mathewson
authors.forename: Shin-Rong Julia
authors.initials: SJ
authors.lastname: Wu
authors.forename: Corinne
authors.initials: C
authors.lastname: Rossi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D011485:Protein Binding; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10