A role for epigenetic changes in the development of retinal neurodegenerative conditions

Abstract

The study of epigenetic changes is experiencing a period of explosive growth, in part, due to the fact that epigenetic regulation has been linked to everything from cancer to obesity and from tissue differentiation to degeneration. An epigenetic change is an inheritable change in gene expression caused by mechanisms that do not include changes to the DNA sequence of the cell but rather changes to the chromatin structure and its interactions with various nuclear factors. Chromatin’s simplest unit is the nucleosome, which is composed of approximately 147 bp of DNA wrapped around a core of histone proteins. The histone core contains two each of histones H2A, H2B, H3, and H4. While the vast majority of the histone core has a globular, disc-like structure, the terminal tails of the histones are largely unstructured and extend out from the globular domains. Epigenetic changes can be split into two main branches—posttranslational modifications (PTMs) of histones and DNA methylation. DNA methylation typically occurs in CpG islands resulting in 5′-methylcytosine. DNA methylation plays a role in stem cell differentiation and development and is largely associated with gene silencing [1, 2]. PTMs of histones are much more diverse chemically and include acetylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation, and biotinylation [3]. PTMs of histones occur predominantly in the flexible N- and C-terminal tails of the nucleosomal core histone proteins, but they have also been found within the globular domain, as well as in the H1 linker histone [4, 5]. Histone modifications can have both cis and trans effects on nucleosomal arrangement. Changes in histones that directly alter their interaction with DNA or modify higher order chromatin structure are defined as cis effects [6]. The best characterized example of a cis effect is the change in charge on lysine residues following acetylation. The change from positive to neutral is theorized to weaken the association between the histone core and DNA, thereby making the DNA more accessible to transcription factors [7]. Conversely, trans effects are those that alter the association between the chromatin and any of a variety of nuclear complexes, often through the use of special protein domains that recognize various histone PTMs, such as the bromodomain of PCAF, a histone acetyltransferase, that specifically recognizes and binds acetylated lysine residues [8]. These specific changes are thought to create a specific “histone language” that provides both positive and negative signals that govern the binding of specific transcriptional molecules to different cis-regulatory modules on gene promoters [9]. Since modules can independently alter the temporal and tissue-specific expression of select genes [10], PTMs of histones are becoming recognized as a critical part of cell specification and differentiation during development. This review will largely focus on the effect of histone modifications, particularly changes in acetylation, on ocular diseases, many of which involve the apoptotic loss of neurons. Because one of the hallmarks of apoptotic cell death is a widespread change in gene expression, epigenetic modifications in dying cells provide a feasible explanation for how the expression of a large number of genes with diverse regulatory elements may be rapidly adjusted.