c-Myb and GATA-3 cooperatively regulate IL-13 expression via conserved GATA-3 response element and recruit mixed lineage leukemia (MLL) for histone modification of the IL-13 locus.
The c-Myb and GATA-3 transcription factors play important roles in T cell development. We recently reported that c-Myb, GATA-3, and Menin form a core transcription complex that regulates GATA-3 expression and ultimately Th2 cell development in human peripheral blood T cells. However, c-Myb roles for Th2 cytokine expression were not demonstrated. In this article, we report that c-Myb and GATA-3 cooperatively play an essential role in IL-13 expression though direct binding to a conserved GATA-3 response element (CGRE), an enhancer for IL-13 expression. c-Myb and GATA-3 were shown to activate the CGRE-IL-13 promoter by ∼160-fold, and mutation of the canonical Myb binding site completely abrogated CGRE enhancer activity. In contrast, mutation of the GATA binding site partially decreased CGRE enhancer activity. GATA-3 did not bind to CGRE when c-myb expression was silenced. c-Myb, GATA-3, Menin, and mixed lineage leukemia (MLL) bound to CGRE in human primary CD4(+) effector/memory cells. Moreover, c-myb silencing significantly decreased both methylation of histone H3K4 and acetylation of histone H3K9 at the IL-13 locus in CD4(+) effector/memory cells. Therefore, in addition to the strong enhancer effect for the transcription of IL-13, the c-Myb/GATA-3 complex recruits MLL to the CGRE for histone modification of the IL-13 locus during the differentiation of memory Th2 cells.
Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Teruhiko
T
Kozuka
Mayumi
M
Sugita
Susan
S
Shetzline
Alan M
AM
Gewirtz
Yuji
Y
Nakata
D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D006657:Histones; D018793:Interleukin-13; D020598:Proto-Oncogene Proteins c-myb; D051788:Myeloid-Lymphoid Leukemia Protein