Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:DNA methylation and not allelic variation regulates STAT6 expression in human T cells. 1994 30

Bovine leukemia virus (BLV) proviral latency represents a viral strategy to escape the host immune system and allow tumor development. Besides the previously demonstrated role of histone deacetylation in the epigenetic repression of BLV expression, we showed here that BLV promoter activity was induced by several DNA methylation inhibitors (such as 5-aza-2'-deoxycytidine) and that overexpressed DNMT1 and DNMT3A, but not DNMT3B, down-regulated BLV promoter activity. Importantly, cytosine hypermethylation in the 5'-long terminal repeat (LTR) U3 and R regions was associated with true latency in the lymphoma-derived B-cell line L267 but not with defective latency in YR2 cells. Moreover, the virus-encoded transactivator Tax(BLV) decreased DNA methyltransferase expression levels, which could explain the lower level of cytosine methylation observed in the L267(LTaxSN) 5'-LTR compared with the L267 5'-LTR. Interestingly, DNA methylation inhibitors and Tax(BLV) synergistically activated BLV promoter transcriptional activity in a cAMP-responsive element (CRE)-dependent manner. Mechanistically, methylation at the -154 or -129 CpG position (relative to the transcription start site) impaired in vitro binding of CRE-binding protein (CREB) transcription factors to their respective CRE sites. Methylation at -129 CpG alone was sufficient to decrease BLV promoter-driven reporter gene expression by 2-fold. We demonstrated in vivo the recruitment of CREB/CRE modulator (CREM) and to a lesser extent activating transcription factor-1 (ATF-1) to the hypomethylated CRE region of the YR2 5'-LTR, whereas we detected no CREB/CREM/ATF recruitment to the hypermethylated corresponding region in the L267 cells. Altogether, these findings suggest that site-specific DNA methylation of the BLV promoter represses viral transcription by directly inhibiting transcription factor binding, thereby contributing to true proviral latency.
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PMID:DNA cytosine methylation in the bovine leukemia virus promoter is associated with latency in a lymphoma-derived B-cell line: potential involvement of direct inhibition of cAMP-responsive element (CRE)-binding protein/CRE modulator/activation transcription factor binding. 2041 92