Fig. 7

A schematic diagram of molecular mechanisms showing how CREB promotes GDNF transcription in GBM cells as a cofactor for DNA methylation and histone acetylation. a In normal astrocytes, GDNF silencer II is not methylated, and pCREB binds to the CRE in enhancer II and silencer II. Binding of pCREB to the CRE in silencer II is significantly higher in normal astrocytes than in GBM cells. Binding of pCREB to CRE in silencer II activates the silencing action of silencer II and reduces GDNF expression. b In GBM cells, CREB is significantly upregulated and phosphorylated. Hypermethylation of silencer II, especially the CRE, inhibits its binding to pCREB, thereby increasing the binding of pCREB to CRE in enhancer II. pCREB recruits CBP to enhancer II and the TSS, enhances histone H3 acetylation and RNA polymerase II recruitment at these sites, and ultimately leads to high GDNF transcription. The letters P and A stand for phosphorylation and acetylation, respectively. The bat structure represents DNA methylation. Blue cylinders represent nucleosomes. Red lines indicate histone N-termini