Epigenetics rules

C.H. Waddington introduced term “epigenetic” in his 1939 work [1] as an explanation of the differentiation of embryonic cells into functionally distinct tissues and cell types despite all cells having identical chromosomes. During the following more than 70 years, this term evolved to “epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence” [2]. In this thematic issue of the Journal of Ocular Biology, Diseases, and Informatics (JOBDI) on the subject of “The role of epigenetics and chromatin structure in ocular development and diseases” we will focus on the original Waddington's meaning of epigenetics as a mechanism underlying tissue specification during development and tissue maintenance in adulthood and how changes in this mechanism could lead to diseases.

DNA in the cell is packed into nucleosomes, the primary units of chromatin. Nucleosomes consist of 147 bp of DNA wrapped around histone octamers and separated by 10–100 bp of relatively straight linker DNA. Any changes in binding of DNA of a gene to histones or to other non-histone chromatin proteins will alter chromatin structure of this gene and lead to changes in functional state of the gene in the genome. Genes can be in one of several functional states: transcribed, poised for transcription, inactivated, and silenced. Transition of a gene from one functional state to another involves epigenetic alteration of nucleosomes located mainly at the transcriptional start site or some other regulatory sequences in or close to the gene. These epigenetic changes could be achieved by six primary mechanisms:

• 1. DNA methylation

• 2. Chromatin remodeling by chromatin-associated proteins

• 3. Histone modifications

• 4. Histone variants and their composition

• 5. Non-coding regulatory RNAs

• 6. Chromatin 3D structure including DNA looping and nuclear territories

Epigenetic rules for tissue development are only beginning to emerge now. During mammalian development, at the time of tissue specification, the cells cease to proliferate. This is with an accompanied by a dramatic downregulation of genes responsible for cell cycle progression and in the resulting post-mitotic cells large numbers of tissue-specific genes are upregulated to give the mature phenotype. In addition, genetic inactivation of many chromosomal loci at the end of tissue maturation correlates with formation of compact block of heterochromatin. A mature tissue needs to keep its genes in right functional states by maintaining homeostasis of epigenetic processes. Disturbance of such a balance could lead to alterations of gene transcription and ultimately to pathogenic conditions and disease.

In this thematic issue of JOBDI, four reviews are focused on what is known about epigenetic regulation during eye development and disease, mostly using retina as an example. The retina begins as an early compartment of the forebrain and has frequently served as a model of CNS development [3, 4]. Retinal cell types are formed in a characteristic sequence from E12 to PN5 with ganglion cells, amacrine cells, and horizontal cells among the early formed types and rod photoreceptors and bipolar cells formed predominantly during the later postnatal period.

One of the epigenetic mechanisms, namely the regulation of gene expression by DNA methylation, is subject of a review by D.C. Otteson “Eyes on DNA methylation: current evidence for DNA methylation in ocular development and disease”. The author summarizes historical perspectives in the field and discusses new genome-wide technologies that should help future researchers to determine species/tissue-specific patterns of DNA methylation and relate them to gene expression during development and disease. The author describes how DNA methylation on CpG islands and the shores could regulate a gene and emphasizes roles of DNMTs and methyl binding proteins. As it is mentioned in this review, the body of published research on regulation of ocular gene expression by DNA methylation is small when compared to the literature related to methylation in other tissues. Nevertheless, we may hope that continued development of high throughput strategies to map genome-wide changes in DNA methylation has a strong potential to reveal new roles for DNA methylation in regulating gene expression in the eye during development, aging, and disease.

Another way of epigenetic regulation could be achieved through chromatin remodeling proteins and they are subject of review by P.S. Lagali and D.J. Piketts “Matters of the life and death: role of chromatin remodeling proteins in retinal neuron survival”. Authors summarize the role of epigenetic factors in mediating neuronal homeostasis and survival for protection against cell death and neurodegenerative conditions. They pointed out that despite an increasing number of studies describing interactions between transcription factors that control development of the retina and various chromatin remodeling proteins, much less attention was given to epigenetic regulation of retinal neuron maintenance and homeostasis. Review emphasizes the importance of strict control of chromatin dynamic for cellular homeostasis and physical and function integrity of neurons. The authors stress importance of studying neuroprotective mechanisms and cell surviving “strategies” because these findings may enable the development of novel therapeutics for treating human retinal degenerative conditions.

Changes in histone post-translation modifications underlie one of the most widely studied mechanisms of epigenetic regulation. Histone acetylation has been the most extensively studied chromatin modification in the context of neurodegenerative processes. The review article “A role for epigenetic changes in the development of retina degenerative conditions” by H.R. Pelzel and R.W. Nickells describes epigenetic alterations in the retina during ocular diseases, many of which involve apoptotic loss of neurons. This review is focused on the effects of histone modifications, particularly changes in acetylation and the importance of a right balance between two classes of enzyme that maintain histone acetylation level, HATs and HDACs, for cell survival during injury or neurodegeneration.

The review article “Epigenetic Regulation of Retinal Development and Disease” by Rao R.C., Henning A.K., Malik M.T.A., Chen D.F., and Chen S. summarizes major current findings in different mechanisms of epigenetic regulation that include DNA methylation, histone modifications, and chromosomal organization. This work shows how these mechanisms are linked to the development and maintenance of retinal structure and function, with focus on ganglion cells and photoreceptors. The authors describe several histone modifications in retinal ganglion cells (RGC) and choroidal melanocytes that include methylation, acetylation, and ubiquitination, as well as DNA methylation in RGC. Chromatin modifications in retinal photoreceptors are described in this review using several photoreceptor genes, particularly the opsin genes, as examples. In these genes, the transcription is regulated by multiple epigenetic mechanisms that include histone modifications and intra-chromosomal looping of enhancer to promoter. Additionally authors emphasize importance of epigenetic regulation through maintenance of chromatin territories and nuclear architecture of such highly specific cells as mammalian rod photoreceptors. In the conclusion, the review points out that the mechanisms of transcriptional and epigenetic regulation are themselves varied and highly complex. Future studies are needed to catalogue the vast number of regulatory events that occur in retina as well as to understand the precise underlying mechanisms that are involved.

Our thematic issue of JOBDI is not intended to be an exhaustive review of epigenetic regulation in the retina. Other important topics, such as the roles of non-coding RNAs have been reviewed recently and can be found elsewhere “Non-coding RNAs in retina development” by Maiorano N.A. and Hindges R. [5].

In conclusion, we would like to stress out the importance of studying the role of epigenetics and chromatin structure in ocular development and diseases, as it was laid down in one of the review in this issue: “The ultimate goal of this research is to understand basic principles of retinal neuron development and behavior and, ultimately, to establish epigenetic biomarkers for human diseases and to identify new targets for the treatment of retinal degenerative disorders and new methods for their prevention” [6].