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.

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

“…41 These data suggest that epigenetics plays a dynamic role in the relationship between HPA axis dysregulation and psychopathology even outside of a developmental sensitive period. Given the need for epigenetic mechanisms in normal brain functioning, 42 we…”

Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer

“…Recent studies showed that miR-329 is upregulated in the brain of a mouse model of Rett syndrome; these mice have mutations in the MeCP2 gene, and the MeCP2 level is elevated in neoplastic breast tissues. [27][28][29] To test the possibility that MeCP2 is responsible for the downregulation of miR-329 in breast cancer, we assessed miR-329 expression after transfection of Mecp2 siRNA into MCF7 cells. As shown in Figure 6d, downregulation of MeCP2 resulted in upregulation of miR-329.…”

Epigenetic mechanisms: A possible link between autism spectrum disorders and fetal alcohol spectrum disorders

“…Experimental evidence has shown that the mammalian transcriptome includes a number of noncoding RNAs (ncRNAs), such as short-noncoding RNAs (sncRNAs), microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), which have been implicated in epigenetic silencing of specific genes [48,49]. Recent data demonstrate that ncRNAs are abundantly transcribed from the human genome, enriched in the brain, and have fundamental regulatory functions in neurogenesis and brain function [50].…”