A putative role for lncRNAs in epigenetic regulation of memory

Abstract

The central dogma of molecular genetics is defined as encoded genetic information within DNA, transcribed into messenger RNA, which contain the instructions for protein synthesis, thus imparting cellular functionality and ultimately life. This molecular genetic theory has given birth to the field of neuroepigenetics, and it is now well established that epigenetic regulation of gene transcription is critical to the learning and memory process. In this review, we address a potential role for a relatively new player in the field of epigenetic crosstalk - long non-coding RNAs (lncRNAs). First, we briefly summarize epigenetic mechanisms in memory formation and examine what little is known about the emerging role of lncRNAs during this process. We then focus discussions on how lncRNAs interact with epigenetic mechanisms to control transcriptional programs under various conditions in the brain, and how this may be applied to regulation of gene expression necessary for memory formation. Next, we explore how epigenetic crosstalk in turn serves to regulate expression of various individual lncRNAs themselves. To highlight the importance of further exploring the role of lncRNA in epigenetic regulation of gene expression, we consider the significant relationship between lncRNA dysregulation and declining memory reserve with aging, Alzheimer's disease, and epilepsy, as well as the promise of novel therapeutic interventions. Finally, we conclude with a discussion of the critical questions that remain to be answered regarding a role for lncRNA in memory.

Keywords: Aging; Alzheimer's disease; Epigenetics; Epilepsy; Memory; Non-coding RNA.

Figure 1.

Schematic representation of the central dogma (DNA → mRNA → protein) of molecular biology in the neuron as it relates to synapse function and memory.

Figure 2.. Non-coding RNAs.

Non-coding RNA (ncRNA) are functional RNA molecules that are not translated into proteins. ncRNA can be classified into long ncRNAs (lncRNAs) and Small ncRNAs. Small ncRNAs include many different RNAs, such as microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), transfer RNA (tRNA), piwi-interacting RNAs (piRNAs) and small interfering RNA (siRNA). lncRNAs are the most ubiquitous and functionally diverse class, they include linear lncRNAs and circular RNAs (circRNAs).

Figure 3.. Epigenetic mechanisms of gene expression regulation.

Several types of epigenetic mechanisms play a role in gene regulation, including (1) DNA methylation of gene promoter regions reflect that gene transcriptional activity; if the promoter region is hypermethylated then the gene transcription is repressed, and vice versa, hypomethylated promoter region favors active genes. In this reaction, DNA methyltransferases (DNMTs) modulate gene transcription via the addition of methyl group to the fifth position of cytosines to be converted to 5-methylcytosine (5mC), which then can be demethylated via ten-eleven translocation (TET) dioxygenase to 5-hydroxymethylcytosine (5-hmC) → 5-formylcytosine (5-fC) → 5-carboxycytosine (5-caC). (2) The post-translational modifications (PTMs) of the histone proteins by methylation on lysine or arginine, phosphorylation on serine or threonine residues, ubiquitylation of lysines, acetylation, and deacetylation of lysines. Histone tails can be modified by “writer” enzymes that catalyze the addition of epigenetic marks on histone tails such as histone acetyltransferases (HATs), histone methyltransferases (HMTs), and Kinases, and removed by “eraser” enzymes, such as histone deacetylases (HDACs), histone demethylases (HDMs) and Protein phosphatase (PPs); Histone variant functions is mediated via in histone variant exchange and turnover.

Figure 4.. Proposed Molecular Functions of lncRNA in memory disorders.

lncRNAs contribute to numerous processes necessary for cellular function and homeostasis. As a result, aberrant expression of lncRNAs seen in disease can significantly alter cellular function resulting in impaired learning and memory. See text for detailed discussion.