MicroRNAs (miRNAs) are a class of small, well-conserved noncoding RNAs that regulate gene expression post-transcriptionally. They have been demonstrated to regulate a lot of biological pathways and cellular functions. Many miRNAs are dynamically regulated during central nervous system (CNS) development and are spatially expressed in adult brain indicating their essential roles in neural development and function. In addition, accumulating evidence strongly suggests that dysfunction of miRNAs contributes to neurological diseases. These observations, together with their gene regulation property, implicated miRNAs to be the key regulators in the complex genetic network of the CNS. In this review, we first focus on the ways through which miRNAs exert the regulatory function and how miRNAs are regulated in the CNS. We then summarize recent findings that highlight the versatile roles of miRNAs in normal CNS physiology and their association with several types of neurological diseases. Subsequently we discuss the limitations of miRNAs research based on current studies as well as the potential therapeutic applications and challenges of miRNAs in neurological disorders. We endeavor to provide an updated description of the regulatory roles of miRNAs in normal CNS functions and pathogenesis of neurological diseases.

It was previously demonstrated that microRNA-199a (miR-199a) was down-regulated in testicular germ cell tumor (TGCT) partially caused by hypermethylation of its promoter. miR-199a is encoded by two loci in the human genome, miR-199a-1 on chromosome (Chr) 19 and miR-199a-2 on Chr 1. Both loci encode the same miR-199a. Another microRNA, microRNA-214 (miR-214), also locates on Chr 1. Previous study revealed that it is co-transcribed with miR-199a-2. However, the biological significance of the co-expression of miR-199a and miR-214 remains largely unknown. In this study, we determined that miR-199a and miR-214 were concordantly expressed in NT2 cells and TGCT patient tissues. After 5-aza treatment, miR-199-3p/5p and miR-214 expression was significantly increased. Silencing of DNMT1with siRNA restored the expression of miR-199a and miR-214, accompanied by de-methylation of the promoters of miR-199a-1/2. TP53 down-regulated the expression of DNMT1 in NT2 cells and overexpression of TP53 restored the expression of miR-199-3p/5p and miR-214. In addition, silencing of PSMD10 up-regulated the expression of TP53, while miR-214 over-expression resulted in PSMD10 down-regulation and TP53 up-regulation. Collectively, our findings highlighted a miR-199a/miR-214/PSMD10/TP53/DNMT1 self-regulatory network, which might be a potential therapeutic target in the treatment of TGCT.

DNA methylation is an important form of epigenetic regulation in both normal development and cancer. Methyl-CpG-binding domain protein 1 (MBD1) is highly related to DNA methylation. Its MBD domain recognizes and binds to methylated CpGs. This binding allows it to trigger methylation of H3K9 and results in transcriptional repression. The CXXC3 domain of MBD1 makes it a unique member of the MBD family due to its affinity to unmethylated DNA. MBD1 acts as an epigenetic regulator via different mechanisms, such as the formation of the MCAF1/MBD1/SETDB1 complex or the MBD1-HDAC3 complex. As methylation status always changes along with carcinogenesis or neurogenesis, MBD1 with its interacting partners, including proteins and non-coding RNAs, participates in normal or pathological processes and functions in different regulatory systems. Because of the important role of MBD1 in epigenetic regulation, it is a good candidate as a therapeutic target for diseases.