What we do
Our research interest is to understand the role of post-transcriptional gene regulation during cell differentiation and stress, with a special interest in male germ cells. Dysregulation of gene expression at the post-transcriptional level leads to growth defects and cancer. Normal tissue development depends on RNA binding proteins and non-coding RNAs; however, more recently, modifications to the RNAs have also been shown to be critical in this process. The functional relevance of RNA modifications in vivo is largely unexplored, and their role in organogenesis and disease remains to be established. A critical type of post-transcriptional modification is the non-templated addition of nucleotides to the 3’ end of RNAs. These 3’ additions of nucleotides are catalysed by enzymes known as terminal nucleotidyl transferases (TENTs). There are eleven mammalian TENTs each one with a preference for one or more of the four ribonucleotides; A, C, G or U. When a TENT adds several Us to an mRNA, a process known as oligo-uridylation, the RNA becomes unstable. Instead, when an mRNA is poly-adenylated, it becomes translationally active. The roles of C terminal additions (cytidylation) and G terminal additions (guanylation) are only now beginning to be explored ex vivo. By systematically studying the TENTs using animal models and advanced molecular biology techniques, we will begin to understand the physiological relevance of terminal modifications in tissue development and start to bridge the gap between our mechanistic knowledge of gene regulation at the cellular level and the principles that define multicellular organization.
In this study, we investigate the critical role of Terminal Oligo Pyrimidine (TOP) Transcripts in stem cell differentiation. Using the P19 embryonal carcinoma cell line as a model, we analyzed protein synthesis and gene expression to understand how these cells transition into specialized types. Our research reveals that TOP Transcripts, characterized by a unique 5' terminal Oligo Pyrimidine motif, display distinctive stability and translational behavior. This stability is closely related to changes in the lengths of their polyA tails, highlighting a crucial post-transcriptional regulatory mechanism. Our findings offer valuable insights into stem cell biology and lay the foundation for future work in regenerative medicine. The accompanying video provides an accessible overview of these processes and their implications. Baptissart, M., Papas, B. N., Chi, R. P. A., Li, Y., Lee, D., Puviindran, B., & Morgan, M. (2023). A unique poly (A) tail profile uncovers the stability and translational activation of TOP transcripts during neuronal differentiation. Iscience, 26(9).DOI: 10.1016/j.isci.2023.107511
Our lab is proud to announce the publication of our first paper, which investigates the processing of a mouse coronavirus RNA during infection. We explored if coronaviruses exhibit poly-A terminal additions like uridylation or guanylation, similar to previous findings on influenza viruses. Utilizing a splint ligation protocol and nanopore sequencing, we discovered that terminal uridylation is prevalent in coronavirus RNA. Poly-A tail lengths and uridylation patterns change as the infection progresses. We found that TUT4 and TUT7, which promote short-tailed uridylation of subgenomic RNAs, lead to transcript decay and reduced viral load, impacting virus replication capacity. This study enhances our understanding of RNA processing and the potential role of TUTs proteins in delaying viral replication. Congratulations to Ankit Gupta, the lead author, and the entire lab for their hard work and dedication. Gupta, A., Li, Y., Chen, S. H., Papas, B. N., Martin, N. P., & Morgan, M. (2023). TUT4/7-mediated uridylation of a coronavirus subgenomic RNAs delays viral replication. Communications Biology, 6(1), 438. https://doi.org/10.1038/s42003-023-04814-1