title: Chromatin dynamics of gene activation and repression in response to interferon alpha (IFN(alpha)) reveal new roles for phosphorylated and unphosphorylated forms of the transcription factor STAT2.
abstract: Signal transducer and activator of transcription 2 (STAT2), the critical component of type I interferons signaling, is a prototype latent cytoplasmic signal-dependent transcription factor. Activated tyrosine-phosphorylated STAT2 associates with STAT1 and IRF9 to bind the ISRE elements in the promoters of a subset of IFN-inducible genes (ISGs). In addition to activate hundreds of ISGs, IFNα also represses numerous target genes but the mechanistic basis for this dual effect and transcriptional repression is largely unknown. We investigated by ChIP-chip the binding dynamics of STAT2 and "active" phospho(P)-STAT2 on 113 putative IFNα direct target promoters before and after IFNα induction in Huh7 cells and primary human hepatocytes (PHH). STAT2 is already bound to 62% of our target promoters, including most "classical" ISGs, before IFNα treatment. 31% of STAT2 basally bound promoters also show P-STAT2 positivity. By correlating in vivo promoter occupancy with gene expression and changes in histone methylation marks we found that: 1) STAT2 plays a role in regulating ISGs expression, independently from its phosphorylation; 2) P-STAT2 is involved in ISGs repression; 3) "activated" ISGs are marked by H3K4me1 and H3K4me3 before IFNα; 4) "repressed" genes are marked by H3K27me3 and histone methylation plays a dominant role in driving IFNα-mediated ISGs repression.
authors.affiliation: Laboratory of Gene Expression, Fondazione A. Cesalpino, 00161 Rome, Italy. barbara.testoni@uniroma1.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Testoni
authors.forename: Christine
authors.initials: C
authors.lastname: Völlenkle
authors.forename: Francesca
authors.initials: F
authors.lastname: Guerrieri
authors.forename: Sabine
authors.initials: S
authors.lastname: Gerbal-Chaloin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020218:Response Elements; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D006657:Histones; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human