Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

  • Shu Horiuchi
    Department of Immunology, Graduate School of Medicine, Chiba University , Chiba 260-8670 ,
  • Atsushi Onodera
    Department of Immunology, Graduate School of Medicine, Chiba University , Chiba 260-8670 ,
  • Hiroyuki Hosokawa
    Department of Immunology, Graduate School of Medicine, Chiba University , Chiba 260-8670 ,
  • Yukiko Watanabe
    Department of Immunology, Graduate School of Medicine, Chiba University , Chiba 260-8670 ,
  • Tomoaki Tanaka
    Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University , Chiba 260-8670 ,
  • Sumio Sugano
    Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo , Chiba 277-8562 ,
  • Yutaka Suzuki
    Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo , Chiba 277-8562 ,
  • Toshinori Nakayama
    Department of Immunology, Graduate School of Medicine, Chiba University , Chiba 260-8670 ,

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<jats:title>Abstract</jats:title> <jats:p>Differentiation of naive CD4 T cells into Th2 cells is accompanied by chromatin remodeling and increased expression of a set of Th2-specific genes, including those encoding Th2 cytokines. IL-4–mediated STAT6 activation induces high levels of transcription of GATA3, a master regulator of Th2 cell differentiation, and enforced expression of GATA3 induces Th2 cytokine expression. However, it remains unclear whether the expression of other Th2-specific genes is induced directly by GATA3. A genome-wide unbiased chromatin immunoprecipitation assay coupled with massive parallel sequencing analysis revealed that GATA3 bound to 1279 genes selectively in Th2 cells, and 101 genes in both Th1 and Th2 cells. Simultaneously, we identified 26 highly Th2-specific STAT6-dependent inducible genes by DNA microarray analysis-based three-step selection processes, and among them 17 genes showed GATA3 binding. We assessed dependency on GATA3 for the transcription of these 26 Th2-specific genes, and 10 genes showed increased transcription in a GATA3-dependent manner, whereas 16 genes showed no significant responses. The transcription of the 16 GATA3-nonresponding genes was clearly increased by the introduction of an active form of STAT6, STAT6VT. Therefore, although GATA3 has been recognized as a master regulator of Th2 cell differentiation, many Th2-specific genes are not regulated by GATA3 itself, but in collaboration with STAT6.</jats:p>

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