Epigenetic regulation of retinal development and disease

Abstract

Epigenetic regulation, including DNA methylation, histone modifications, and chromosomal organization, is emerging as a new layer of transcriptional regulation in retinal development and maintenance. Guided by intrinsic transcription factors and extrinsic signaling molecules, epigenetic regulation can activate and/or repress the expression of specific sets of genes, therefore playing an important role in retinal cell fate specification and terminal differentiation during development as well as maintaining cell function and survival in adults. Here, we review the major findings that have linked these mechanisms to the development and maintenance of retinal structure and function, with a focus on ganglion cells and photoreceptors. The mechanisms of epigenetic regulation are highly complex and vary among different cell types. Understanding the basic principles of these mechanisms and their regulatory pathways may provide new insight into the pathogenesis of retinal diseases associated with transcription dysregulation, and new therapeutic strategies for treatment.

A Synthetic Transcriptional Activator of Genes Associated with the Retina in Human Dermal Fibroblasts

“…Epigenetic modificationss uch as histonea cetylation play an important role in regulating appropriate gene expression that aids in the correct functioning of the retina without any complications. [4] However,h istoned eacetylases such as HDAC2 and HDAC3h ave been reported to induce the deatho fr etinal ganglion cells (RGCs) by inhibiting the expressiono fc rucial RGC genes. [4,22] Several nonspecific HDAC inhibitors (e.g.,s odium butyrate,v alproica cid, [4,23] and trichostatin A [24] )h ave indicated positive effects by shielding the retina against disorders.…”

“…[4] However,h istoned eacetylases such as HDAC2 and HDAC3h ave been reported to induce the deatho fr etinal ganglion cells (RGCs) by inhibiting the expressiono fc rucial RGC genes. [4,22] Several nonspecific HDAC inhibitors (e.g.,s odium butyrate,v alproica cid, [4,23] and trichostatin A [24] )h ave indicated positive effects by shielding the retina against disorders. However,t he application of HDAC inhibitors in treating retinal diseases hasd isadvantagesi nt erms of selectivity because they modify histones at ag loball evel, causing detrimental side effects.…”

“…[1] Ag ene that is regulated in a tissue-specific fashion is thought to be surrounded by aspecific chromatin environment in which the distribution of ah igh level of histone acetylation triggers the active transcription of the corresponding genes. [4] Definedc ontrol to regulate the gene expression induced by HDAC inhibitors can be achievedbyproviding aDNA-recognition motif based on apyrrole-imidazole polyamide (PIP) system. [3] HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA)a nd trichostatin Aa re potentiala gentsf or epigenetic therapy.T hese agentsc an induce globalh istone acetylation, although their mode of action on the target is nonspecific.…”

“…[4] However,h istoned eacetylases such as HDAC2 and HDAC3h ave been reported to induce the deatho fr etinal ganglion cells (RGCs) by inhibiting the expressiono fc rucial RGC genes. [4] However,h istoned eacetylases such as HDAC2 and HDAC3h ave been reported to induce the deatho fr etinal ganglion cells (RGCs) by inhibiting the expressiono fc rucial RGC genes.…”

“…[3] HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA)a nd trichostatin Aa re potentiala gentsf or epigenetic therapy.T hese agentsc an induce globalh istone acetylation, although their mode of action on the target is nonspecific. [4] Definedc ontrol to regulate the gene expression induced by HDAC inhibitors can be achievedbyproviding aDNA-recognition motif based on apyrrole-imidazole polyamide (PIP) system. When binding to their corresponding Watson-Crick base pairs, hairpin PIPs bind to the minor groove in DNA in accordance with ap roposed DNA-pairing rule.…”