The RNA Epigenetics of Retina Cell Development

Epigenetics is the process by which genes turn on or off. Epigenetic processes are instrumental in driving stem cells to become mature, specialized cells. Those on/off instructions may be altered in different phases and cellular compartments during cellular development, including when the instructions in DNA are copied into RNA (transcription), and when RNA is converted into proteins (translation).

Like DNA and histones (the proteins which DNA can wrap around), RNA can be modified by methyl groups, ultimately affecting the level at which the corresponding gene is expressed. The study of how RNA is methylated to affect gene expression is called “epitranscriptomics” or “RNA epigenetics”.

Scientists have only recently begun to investigate the epigenetics associated with RNA. Kellogg’s Rajesh Rao, M.D., an expert in DNA epigenetics, has received one of the first research grants ever awarded for RNA epigenetics in ophthalmology.

The Career Advancement Award from Research to Prevent Blindness (RPB) will support Dr. Rao’s foundational studies of the RNA epigenetics through which a stem cell becomes a retina cell.

Dr. Rao’s team is focusing on a protein called METTL3. “We know that METTL3 plays an important role in directing pluripotent stem cells (PSCs) to become retina cells,” Dr. Rao explains. A PSC is not yet fully developed, and still has the potential to become any type of cell in the body.

“Our hypothesis is that METTL3 encourages retina cell development by methylating RNA, which affects the stability of the transcript,” he continues. “We hope to learn more about this and potentially other roles METTL3 plays in impacting gene expression during this critical window in the formation of the retina.”

Dr. Rao plans a series of studies employing genetically engineered mouse models in which the METTL3 gene is disabled in the retina and doing the same in retinal organoid models—three-dimensional ‘mini organ’ structures derived from mouse and human PSCs.

“Translating our laboratory findings into clinical interventions is still far in the future,” cautions Dr. Rao. “But we hope these fundamental studies in RNA epigenetics will lay the groundwork to better understand how PSCs become retinal cells, with the goal of harnessing those principles to generate retinal tissues from stem cells more efficiently. Implications of this work could one day be applied to regenerative medicine such as stem cell-based transplants to treat retinal blindness.”