PTB-associated Splicing Factor (PSF) Functions as a Repressor of STAT6-mediated Igϵ Gene Transcription by Recruitment of HDAC1

• Published in: The Journal of biological chemistry 2011-02, Vol.286 (5), p.3451-3459
• Main Authors: Dong, Lijie, Zhang, Xinyu, Fu, Xiao, Zhang, Xianzhi, Gao, Xingjie, Zhu, Mengyu, Wang, Xinting, Yang, ZhenXia, Jensen, Ole Nørregaard, Saarikettu, Juha, Yao, Zhi, Silvennoinen, Olli, Yang, Jie
• Format: Article
• Language: English
• Subjects: Acetylation; Allergic diseases; Cooperativity; Gene expression; Gene silencing; Gene Transcription; Genes, Immunoglobulin; HDAC; HeLa Cells; Histone deacetylase; Histone Deacetylase 1 - metabolism; Histone Modification; Humans; Immunoglobulin E; Immunoglobulin epsilon-Chains - genetics; Inflammation; Interleukin 13; Interleukin 4; Interleukin-4 - pharmacology; Lymphoma; Molecular modelling; Phosphorylation; Promoters; Protein Binding - drug effects; Protein Interaction Mapping; Protein Transport; proteomics; PSF; PTB-Associated Splicing Factor; Repressor Proteins; Repressors; RNA-Binding Proteins - metabolism; RNA-Binding Proteins - physiology; Signal Transduction; splicing factors; STAT6; Stat6 protein; STAT6 Transcription Factor - physiology; Transcription activation; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Trichostatin A; Tyrosine
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.168377

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.