Research on epigenetic transcription factors has shown that a novel study may be applicable for some types of age-related disorders. The cover of Nature, on December 3rd 2020, highlighted the article showing results that certain cells in the retina can re-programme transcription factors to restore youthful characteristics of the mature eye. The research, conducted by investigators in the Department of Genetics, Harvard Medical School, Boston, was developed to use the eye as a model to inquire how brain neurons can restore youthful DNA methylation patterns from epigenetic processes. Regeneration and reversing vision loss may be possible to safely reverse the age of a complex tissue restoring biological function for a future therapeutic application.
Epigenetics, meaning “beyond” genetics, refers to phenotypic changes not coded within DNA but increasingly recognized as a significant process in the regulation of gene expression. Epigenetic processes can regulate gene expression, for example by acting on a gene’s promoter sequence or through chromatin remodelling to alter tertiary structures, which in turn alter access to transcription and enhancer sections of genes. In essence, epigenetic processes act as an editing tool managing which genes are silenced and which are given the stage in a constantly changing inter- and intra-cellular environment. Other epigenetic mechanisms that can impact gene expression include molecular modifications of the DNA, such as DNA methylation, or histone modifications including acetylation, de-acetylation, phosphorylation, and methylation. Numerous studies in recent years have shown how DNA methylation may contribute to a number of retinal research activities.
In the current research, investigators used a strategy to genetically re-engineer certain viruses to induce three Yamanaka transcription factors called OSK (Oct4, Sox2 and Klf4). OSK can provide beneficial effects for reprogramming in axon regeneration and vision applying DNA demethylase (enzymes), TET1 and TET2, catalysing the removal of DNA methylation. This data may “retain a record of youthful epigenetic information – encoded in part by DNA methylation – that can be accessed to improve tissue function and promote regeneration in vivo”. In essence, OSK expression may counteract the negative effects of ageing or axon injury on DNA methylation and these methylation processes alter a broad range of genes involved in neuronal activity. Commenting on their perspective in the journal Nature, Dr. Andrew D. Huberman at the Departments of Neurobiology and Ophthalmology, Stanford University, stated that, “Given that RGCs (retinal ganglion cells) are bona fide brain neurons, there is good reason to think they will. As such, the current findings are bound to ignite great excitement, not only in the field of vision restoration but also in those looking to understand epigenetic reprogramming of neurons and other cell types generally. For decades, it was argued that understanding normal neural developmental processes would one day lead to the tools to repair the aged or damaged brain”.