Two papers published in January from the lab of Wendy Gilbert, PhD, Associate Professor of MB&B, illuminated features guiding the biogenesis and translation of mRNA.
The first paper, “Direct analysis of ribosome targeting illuminates thousand-fold regulation of translation initiation,” was published in Cell Systems on January 17th and led by first author Rachel O.Niederer, an associate research scientist in Gilbert’s group. The study employed a method established by the lab, called DART, which couples high-throughput in vivo approaches with low-throughput in vitro translation reconstitution assays to assess the translational regulatory potential of mRNA variants. Applying DART to 4,354 mRNA isoforms from yeast cell lysates, the researchers determined the basis for up to 1,000-fold differences in ribosome recruitment to the 5′ UTR of mRNA molecules. They found that sequence and length variations in the 5′ UTR impact recruitment of translational control elements and identified both repressive and stimulating translational motifs. Beyond the scope of the study, DART has the potential to facilitate the development of protein-based therapies for diseases.
The second paper, “Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing” was published in Molecular Cell on January 19th. The study revealed that pseudouridine and pre-mRNA-modifying pseudouridine synthases regulate pre-mRNA processing in human cells. Applying single-nucleotide resolution pseudouridine profiling on nascent pre-mRNA, the researchers found that pseudouridine locations overlapped with splice sites and RNA-binding protein sites. Tissue-specific expression of these synthases suggests a regulatory potential for pre-mRNA pseudouridylation by these factors to control human gene expression. First author Nicole Martinez published the study as a postdoctoral fellow in Gilbert’s group. She is now starting her own group as an Assistant Professor at Stanford University, where she will continue investigating splicing regulation by pre-mRNA pseudouridylation.
Upon publication of these works, the Gilbert Lab received a $1.7 million grant from Pfizer, maker of the widely distributed Pfizer‑BioNTech COVID‑19 Vaccine. The grant is intended to facilitate continued research on mRNA properties and functions in cellular homeostasis for therapeutic potential.
By Brigitte Naughton