Yale Lab Offers New Insights into mRNA Lifecycle and Regulation

mRNA has entered the public lexicon thanks to the successful rollout of COVID-19 vaccines, but two new papers out of Wendy Gilbert’s lab at Yale University show that there is still much to be learned about its lifecycle and biological roles within a cell.

Because mRNAs carry directions from the cell’s DNA to the ribosomes, which produce proteins involved in life functions, they garner significant attention in research. The COVID-19 vaccines developed by Pfizer and Moderna contain mRNA-based instructions for cells to produce proteins that recognize spike proteins on the surface of the SARS-Cov-2 virus, making them targets for destruction by the immune system.

In one of the studies, a team led by postdoctoral student Nicole Martinez found that pseudouridine plays a key role in the birth of mRNA by splicing the genetic genetic material that creates it. These findings shed new light on the origins of diseases linked to variants of pseudouridine such as mitochondrial myopathy, digestive disorders, intellectual disability, and resistance to viral infection. Several cancers have been also linked to elevated levels of pseudouridine, suggesting that faulty splicing of mRNAs may trigger tumor formation and cancer metastasis. This work, “Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing,” was published in Molecular Cell.

The second paper, “Direct analysis of ribosome targeting illuminates thousand-fold regulation of translation initiation,” was published in the journal Cell Systems. It investigated how ribosomes know how many proteins to produce from the genetic instructions they receive from mRNAs. The team, led by Rachel Niederer, an associate research scientist in Gilbert’s lab, developed a new technology called direct analysis of ribosome targeting (DART) to find regulatory elements that can instigate or stop the production of proteins by ribosomes. The findings could allow scientists to significantly modify protein production rates, which could help adjust dosing in future mRNA vaccines.

Gilbert says the technology could also be applied to development of any protein-based therapies for a multitude of diseases.