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)

DNA demethylation of astrocyte-specific gene promoters and STAT3 activation in neural precursor cells (NPCs) are essential for astrogliogenesis in the developing brain. To date, it remains unclear whether DNA methylation is the sole epigenetic determinant responsible for suppressing astrocyte-specific genes. Here, we used mouse embryonic stem cells (TKO ESCs) that lacked all 3 DNA methyltransferase genes, Dnmt1, Dnmt3a, and Dnmt3b, and thereby exhibit complete demethylation of the astrocyte-specific glial fibrillary acidic protein (Gfap) gene promoter. We found that although the Gfap promoter was demethylated, STAT3 failed to bind to its cognate element to induce Gfap transcription, whereas it induced transcription of a different target gene, Socs3. Moreover, although the Gfap promoter region containing the STAT3-binding site (GSBS) is enriched with transcription-repressive histone modifications, such as methylation of H3 at lysine 9 (H3K9me3) and H3K27me3, the reduction of these modifications in TKO ESCs was not sufficient for binding of STAT3 at GSBS. Furthermore, GSBS was digested by micrococcal nuclease in late-gestational NPCs that express GFAP upon LIF stimulation, but not in cells that show no expression of GFAP even in the presence of LIF, indicating that STAT3 can access GSBS in the former cells. We further showed that expression of NF-1A, which is known to potentiate differentiation of mid-gestational NPCs into astrocytes, increased its accessibility. Taken together, our results suggest that chromatin accessibility of GSBS plays a critical role in the regulation of Gfap expression.
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PMID:Chromatin accessibility at a STAT3 target site is altered prior to astrocyte differentiation. 2343 58

Carcinoma-associated fibroblasts (CAF) mediate the onset of a proinvasive tumour microenvironment. The proinflammatory cytokine LIF reprograms fibroblasts into a proinvasive phenotype, which promotes extracellular matrix remodelling and collective invasion of cancer cells. Here we unveil that exposure to LIF initiates an epigenetic switch leading to the constitutive activation of JAK1/STAT3 signalling, which results in sustained proinvasive activity of CAF. Mechanistically, p300-histone acetyltransferase acetylates STAT3, which, in turn, upregulates and activates the DNMT3b DNA methyltransferase. DNMT3b methylates CpG sites of the SHP-1 phosphatase promoter, which abrogates SHP-1 expression, and results in constitutive phosphorylation of JAK1. Sustained JAK1/STAT3 signalling is maintained by DNA methyltransferase DNMT1. Consistently, in human lung and head and neck carcinomas, STAT3 acetylation and phosphorylation are inversely correlated with SHP-1 expression. Combined inhibition of DNMT activities and JAK signalling, in vitro and in vivo, results in long-term reversion of CAF-associated proinvasive activity and restoration of the wild-type fibroblast phenotype.
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PMID:Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. 2666 66