title: Enhanced chromatin accessibility and recruitment of JUNB mediate the sustained IL-4 expression in NFAT1 deficient T helper 2 cells.
abstract: Nuclear factor of activated T cells (NFAT) is a family of transcription factors composed of five proteins. Among them, NFAT1 is a predominant NFAT protein in CD4(+) T cells. NFAT1 positively regulates transcription of a large number of inducible cytokine genes including IL-2, IL-4, IL-5 and other cytokines. However, disruption of NFAT1 results in an unexpected increase of IL-4. In this study, we have investigated the role of NFAT1 in regulation of IL-4 gene expression in T helper 2 cells (Th2) from an epigenetic viewpoint. NFAT1 deficient Th2 cells showed a sustained IL-4 expression while wild type (WT) cells reduced its expression. We tested whether epigenetic maintenance and changes in the chromatin architecture of IL-4 promoter locus play a role in differential IL-4 transcription between in WT and NFAT1 deficient Th2 cells. Compared with WT, NFAT1 deficient CD4(+) Th2 cells exhibited enhanced chromatin accessibility with permissive histone modification and DNA demethylation in the IL-4 promoter region. Transcription factors bound to IL-4 promoter region in the absence of NFAT1 were identified by Micro-LC/LC-MS/MS analysis. Among the candidates, preferential recruitment of JUNB to the IL-4 promoter was confirmed by chromatin immunoprecipitation analysis. Overexpression of JUNB together with SATB1 synergistically upregulated IL-4 promoter activity, while knockdown JUNB significantly reduced IL-4 expression. Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture.
authors.affiliation: School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Jun-Seock
authors.initials: JS
authors.lastname: Son
authors.forename: Chang-Suk
authors.initials: CS
authors.lastname: Chae
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Hwang
authors.forename: Zee Yong
authors.initials: ZY
authors.lastname: Park
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D019169:Jurkat Cells; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000172:deficiency*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D002843:Chromatin; D050778:NFATC Transcription Factors; D016755:Proto-Oncogene Proteins c-jun; C486732:Stab1 protein, mouse; D015847:Interleukin-4