DNA methylation and not allelic variation regulates STAT6 expression in human T cells.
STAT6 transcription factor, which has been implicated in commitment to Th2, is known to be activated by IL-4 and IL-13. Accordingly, STAT6 is primarily responsible for the transcriptional effects of IL-4 and IL-13. STAT6-deficient mice are known to have defective IL-4-mediated functions, such as B cell proliferation, Th2 cell development and IgE secretion; therefore, they primarily contain the Th1 phenotype. However, the mechanism responsible for regulation of STAT6 expression transcriptionally and post-transcriptionally has yet to be elucidated. Here, we characterized the human STAT6 promoter gene and found that the transcriptional regulatory elements CCAAT and ATF were important for the STAT6 promoter activity. Direct sequencing analysis revealed that the 13 GT repeat allelic variation in noncoding exon 1 of the STAT6 gene appeared more frequently in 91 patients with asthma or rheumatoid arthritis than the 15 GT repeat variation, which is the dominant phenotype in healthy controls. However, it appears that this allelic variation did not affect the STAT6 transcriptional activity. Interestingly, treatment with a DNA methyltransferase inhibitor markedly increased the expression of STAT6 mRNA and protein in human primary T cells. In contrast, IFN-gamma treatment significantly repressed the STAT6 transcriptional activity. Therefore, the present study provides insight into the molecular basis of STAT6 expression, and in particular, demonstrates that STAT6 expression is associated with DNA hypermethylation rather than promoter polymorphisms or allelic variations.
Kim
Eu-Gene
EG
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi, Korea.
Shin
Hyun-Jin
HJ
Lee
Chang Geun
CG
Park
Hye-Young
HY
Kim
Yoon-Keun
YK
Park
Heung-Woo
HW
Cho
Sang-Heon
SH
Min
Kyung-Up
KU
Cho
Mi-La
ML
Park
Sung-Hwan
SH
Lee
Chang-Woo
CW
D001172:Arthritis, Rheumatoid / Q000235:genetics; D001249:Asthma / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005786:Gene Expression Regulation; D005787:Gene Frequency; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D050436:Regulatory Elements, Transcriptional; D050800:STAT6 Transcription Factor / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D007371:Interferon-gamma; D008780:Methyltransferases