Study Reveals How Chemical Modifications Guide Stem Cell Development into Retinal Cells

Cells use their DNA as a blueprint to produce mRNA messages, which are later converted into proteins needed for function. The ways a cell reads its DNA vary, influenced by specific chemical modifications to DNA, RNA, or proteins, guiding which messages become proteins. Researchers at the University of Michigan, led by Rajesh C. Rao, conducted a study to understand the chemical cues controlling the development of stem cells into retinal cells. Their work, recently published in Stem Cell Reports, seeks to inform future efforts in creating cells for transplantation and screening drugs for retinal diseases.

Cells finely control the proteins they produce by adding chemical groups onto their DNA or RNA, such as methyl groups, which can destabilize RNA and change the amount of protein produced. “Chemical modifications to RNA have been studied in other areas, including diabetes and cancer,” said Rao, “however, no one had looked at how they affect the process by which stem cells turn into retinal cells.” The team focused on the role of METTL3, a protein responsible for adding methyl groups to RNA. By using genetic modifications, they found that METTL3 must be in the nucleus to drive the transformation of stem cells into retinal cells.

To pinpoint where METTL3 acts, the researchers mapped all RNA regions modified by METTL3 using GLORI, a specialized technique. They then applied RNA engineering to strip modifications from the Six3 gene, which is a key controller for stem cell differentiation into retinal tissue. Their experiments showed that these RNA modifications directly managed the stability of Six3 RNA. Use of a CRISPR system tailored for RNA revealed that changes at the 3' end of RNA were particularly important for Six3 stability. Additionally, suppressing the Ythdf gene family blocked stem cell conversion to retina in a manner similar to METTL3 loss.

“This is the first report to look at the mechanisms of RNA epigenetics, or how chemical modifications in RNA can influence the process of stem cells development into retinal tissue,” Rao explained. The researchers are now pursuing whether METTL3 changes RNA without physically changing DNA shape—a surprising result from this work. They are also investigating if RNA modifications fluctuate in retinal diseases, noting that high sugar levels can influence these modifications. “The retina is a very sensitive tissue and can get damaged quite easily in patients with diabetes and we want to understand whether RNA modifications are involved,” Rao added.