Epilepsy is a common neurologic disorder yet no treatments aimed at preventing epilepsy have been developed. Several molecules including genes containing cAMP response elements (CREs) in their promoters have been identified that contribute to the development of epilepsy, a process called epileptogenesis. When phosphorylated cAMP response element binding protein (CREB) increases transcription from CRE regulated promoters. CREB phosphorylation is increased in rodent epilepsy models, and in the seizure onset region of humans with medically intractable epilepsy (Rakhade, et al., 2005, Lee, et al., 2007, Lund, et al., 2008). Here we show that mice with decreased CREB levels (CREB αΔ mutants) have a ~50% reduction in spontaneous seizures following pilocarpine induced status epilepticus (SE) and require more stimulation to electrically kindle. Following SE, brain derived neurotrophic factor (BDNF) and inducible cAMP early repressor (ICER) mRNAs are differentially up-regulated in the hippocampus and cortex of the CREB αΔ mutants compared to wild-type mice, which may be contributing to differences in the severity of epilepsy. In contrast, we found no difference in KCC2 mRNA levels between the CREB αΔ and wild-type mice after SE. The mechanism by which BDNF and ICER mRNAs increase specifically in the CREB αΔ compared to wild-type mice following SE is not known. We did, however, find an increase in specific cAMP response element modulator (CREM) mRNA transcripts in the CREB αΔ mutants that might be responsible for the differential regulation of BDNF and ICER after SE. Altering CREB activity following a neurologic insult provides a therapeutic strategy for modifying epileptogenesis.

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Recently, the regulatory role of epigenetic modifications in the occurrence and development of malignant tumors has attracted extensive attention. RNA m6A methylation is the most abundant RNA modification in eukaryotic cells and regulates RNA transcription, processing, splicing, degradation, and translation. As important biomarkers, miRNAs play a crucial role in the diagnosis and treatment of diseases as well as in the development of anti-tumor drugs. Recently, increasing evidence has shown that m6A modification plays a vital role in regulating miRNA biosynthesis. We, herein, have reviewed the enzyme system involved in m6A methylation and the crosstalk between m6A modification and miRNAs in cancer. In addition, we have discussed the potential clinical applications and possible development directions of this field in the future.

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