Epigenetics and ncRNAs in brain function and disease: mechanisms and prospects for therapy

Abstract

The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3' untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

Fig. 1

Integration of microRNA and epigenetic regulation pathways. (A) MicroRNAs can regulate the expression of epigenetic modifier genes (such as EZH2 or MECP2) by post-transcriptional gene silencing. MicroRNAs are transcribed as long primary (pri-miRNA) transcripts and then sequentially processed to generate the mature miRNA species. The miRNA RNA induced silencing complex (miRISC, which includes AGO2, Dicer and TARBP2) loaded with a mature miRNA searches the cytoplasm for its cognate target (e.g. the EZH2 or MECP2 mRNA). Silencing of EZH2 or MECP2 expression leads to global alterations in the epigenome. (B) MicroRNA genes are frequently inactivated by epimutations in cancers. Therefore, epigenetic alterations can affect miRNA expression. Black lollipops indicate DNA methylation. (C) Endogenous miRNAs can induce transcriptional gene silencing of complementary target promoters. Pri-miRNAs are processed by the conventional miRNA processing pathway but the mature miRNA species is loaded into AGO1 instead of AGO2. AGO1 is the core component of the RNA Induced Transcriptional Silencing (RITS) complex which also includes HDAC1, SUV39H, EZH2 and DNMT3A. RITS is guided to a complementary promoter-associated RNA by its bound miRNA. Recruitment of RISC induces heterochromatin formation and promoter DNA methylation at the target promoter