title: PTB-associated splicing factor (PSF) functions as a repressor of STAT6-mediated Ig epsilon gene transcription by recruitment of HDAC1.
abstract: Regulation of transcription requires cooperation between sequence-specific transcription factors and numerous coregulatory proteins. In IL-4/IL-13 signaling several coactivators for STAT6 have been identified, but the molecular mechanisms of STAT6-mediated gene transcription are still not fully understood. Here we identified by proteomic approach that the PTB-associated splicing factor (PSF) interacts with STAT6. In intact cells the interaction was observed only after IL-4 stimulation. The IL-4-induced tyrosine phosphorylation of both STAT6 and PSF is a prerequisite for the efficient association of the two proteins. Functional analysis demonstrated that ectopic expression of PSF resulted in inhibition of STAT6-mediated transcriptional activation and mRNA expression of the Igε germline heavy chain gene, whereas knockdown of PSF increased the STAT6-mediated responses. PSF recruited histone deacetylase 1 (HDAC1) to the STAT6 transcription complex, which resulted in reduction of H3 acetylation at the promoter regions of Ig heavy chain germline Igε and inhibition of STAT6-mediated transcription. In addition, the HDACs inhibitor trichostatin A (TSA) enhanced H3 acetylation, and reverted the PSF-mediated transcriptional repression of Igε gene transcription. In summary, these results identify PSF as a repressor of STAT6-mediated transcription that functions through recruitment of HDAC to the STAT6 transcription complex, and delineates a novel regulatory mechanism of IL-4 signaling that may have implications in the pathogenesis of allergic diseases and pharmacological HDAC inhibition in lymphomas.
authors.affiliation: Department of Immunology, Basic Medical College, Tianjin Medical University, Heping District, Qixiangtai Road No. 22, Tianjin 300070, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Dong
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Fu
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Zhang
authors.forename: Xingjie
authors.initials: X
authors.lastname: Gao
authors.forename: Mengyu
authors.initials: M
authors.lastname: Zhu
authors.forename: Xinting
authors.initials: X
authors.lastname: Wang
authors.forename: ZhenXia
authors.initials: Z
authors.lastname: Yang
authors.forename: Ole Nørregaard
authors.initials: ON
authors.lastname: Jensen
authors.forename: Juha
authors.initials: J
authors.lastname: Saarikettu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Olli
authors.initials: O
authors.lastname: Silvennoinen
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
mesh_terms: D005803:Genes, Immunoglobulin; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology; D000072670:PTB-Associated Splicing Factor; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D007139:Immunoglobulin epsilon-Chains; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D056284:Histone Deacetylase 1