Regulatory RNAs and control of epigenetic mechanisms: expectations for cognition and cognitive dysfunction

Abstract

The diverse functions of noncoding RNAs (ncRNAs) can influence virtually every aspect of the transcriptional process including epigenetic regulation of genes. In the CNS, regulatory RNA networks and epigenetic mechanisms have broad relevance to gene transcription changes involved in long-term memory formation and cognition. Thus, it is becoming increasingly clear that multiple classes of ncRNAs impact neuronal development, neuroplasticity, and cognition. Currently, a large gap exists in our knowledge of how ncRNAs facilitate epigenetic processes, and how this phenomenon affects cognitive function. In this review, we discuss recent findings highlighting a provocative role for ncRNAs including lncRNAs and piRNAs in the control of epigenetic mechanisms involved in cognitive function. Furthermore, we discuss the putative roles for these ncRNAs in cognitive disorders such as schizophrenia and Alzheimer's disease.

Keywords: chromatin; epigenetics; long noncoding RNA; neuroplasticity; neuroscience; short noncoding RNA.

Figure 1.. Canonical mechanism of miRNA generation and epigenetic regulation.

(A) Schematic of canonical miRNA biogenesis. Pri-miRNA are transcribed by RNA Pol II, and stem-loop regions are processed by Drosha and DGCR8. The resulting pre-miRNA is exported through the nuclear membrane into the cytoplasm, where Dicer further cleaves the pre-miRNA into a short double-stranded RNA region. A guide strand is selected and bound by AGO within the RISC complex, while the passenger strand is cleaved and degraded. (B) miRNA and siRNA in conjunction with the cytoplasmic RISC complex target proteins involved in epigenetic regulation at the mRNA level. This post-transcriptional silencing, ultimately results in global alterations in the epigenome and cellular function. AGO: Argonaute; CME: Chromatin-modifying enzyme; miRISC: miRNA in complex with RISC; PTM: Post-translational modifications; Pri-miRNA: Primary miRNA; Pre-miRNA: Precursor miRNA; RISC: RNA-induced silencing complex.

Figure 2.. Epigenetic regulation by nuclear short noncoding RNA.

Proposed mechanisms of sncRNA-mediated epigenetic regulation. (A) Studies have demonstrated short non-coding RNA (sncRNA)-mediated targeting of mRNA cotranscriptionally. This results in the recruitment of AGO or PIWI proteins to the gene locus of nascent transcripts and may result in the recruitment of CMEs and epigenetic regulation via DNA methylation or the post-translational modification of associated proteins, such as histones [93,94]. (B) sncRNAs in complex with AGO/PIWI also associate directly with DNA. This results in the recruitment of CMEs and epigenetic regulation [95]. AGO/PIWI indicates a member of either the argonaute or PIWI family of proteins. CME: Chromatin-modifying enzyme; DNMT: DNA methyltransferase; PTM: Post-translational modifications; RNA Pol II: RNA polymerase II.

Figure 3.. Origins of long noncoding RNAs.

(A–E) Many lncRNA genomic loci are colocalized with protein coding genes, and they are often described in relation to these genes. A number of common naming conventions have come into general use to describe the various protein coding gene associated lncRNAs. (A) Antisense transcripts overlap protein coding genes, but are transcribed from the antisense strand. (B) Bidirectional transcripts share transcription start sites with protein coding genes, but are transcribed in the opposite direction. (C) Intergenic transcripts do not overlap with protein coding genes. (D) Overlapping transcripts overlap significantly with or encompass protein coding genes on the sense strand. (E) Intronic transcripts are located within a sense-strand intron of a protein coding gene. Solid bars indicate exons of mRNAs (blue), lncRNAs (red). Diagonal stripes indicate overlapping exons. Chevron arrows indicate introns of mRNAs (blue), lncRNAs (red) or overlapping transcripts (alternating red and blue). Curved arrows indicate transcription start sites.

Figure 4.. lncRNA-mediated epigenetic regulation.

lncRNAs possess a number of mechanisms by which they initiate or facilitate epigenetic regulation, and multiple archetypal functions are often utilized within a single lncRNA transcript. (A) lncRNAs often recruit chromatin-modifying enzymes in cis, thereby mediating epigenetic regulation of nearby genes (dimitrova, zhang, redrup). (B) lncRNAs may also act as guides, targeting associated CMEs to target loci in trans, potentially through direct interaction with target regions. (C) lncRNAs may act as scaffolding factors, and mediate the assembly of ribonucleoprotein complexes with multiple regulatory functions. This may occur either in cis, as occurs with the direct CMEs to target loci in trans. CME: Chromatin-modifying enzyme; DNMT: DNA methyltransferase; PTM: Post-translational modifications; RNA Pol II: RNA polymerase II; RNP complex: Ribonucleoprotein complex.