Transfer-RNAs are tranditionally viewed as a static component of the protein synthesis machinery. Recently, several studies have raised the possibility that tRNAs are more dynamic and can support different cellular states and phenotypes. Although generally debated, some evidence has emerged that tRNA levels in the cell imapct the gene expression landscape in the cell. In a recent study, we demonstrated that the tRNA landscape is drastically modified in highly metastatic cells and that these modulations drive the expression of key promoters of metastasis. These results were published in Cell. You can also read a short preview about this study.
Nucleotide modifications can expand the information content of nucleic acids. The majority of these chemical modifications are largely uncharacterized. The most common base modification of eukaryotic mRNA is methylation of the N6 nitrogen on adenosine referred to (m6A). In two recent papers, we have described the role of m6A RNA modification as a marker for RNA processing. We showed that RNA-binding protein HNRNPA2B1 can preferentially bind this modification and impact miRNA processing and splicing. These results were published in Nature and Cell. You can also read a short blog post about this study.
Cells respond to stress through a variety of mechanisms. In this study, we identified a mechanistically novel post-transcriptional regulatory pathways that protects the cells from pathologic growth and spread. We showed that a novel class of tRNA fragments (tRFs) that are generated under stress in normal and poorly metastatic cells, evade induction in highly metastatic cells. Using mechsnitic in vitro and in vivo experiments, we demonstrated that the oncogenic RNA-binding protein YBX1 is titrated by these fragments, which in turn reduces the expression of the YBX1 regulon. These results were published in the journal Cell and highlighted in Nature Reviews Cancer.
Aberrant regulation of RNA stability has an important role in many disease states. Whole-genome transcript stability measurements in poorly metastatic and highly metastatic breast cancer cells paved the way for the identification of a structural RNA element the presence of which results in higher decay rate in metastatic cells. We subsequently identified the dsRBP TARBP2 as the interacting partner and showed that this RNA-binding protein plays a functional role in promoting breast cancer metastasis. Focused computational and experimental follow-ups revealed that TARBP2 mediates metastasis through destabilization of novel tumor suppressors, ZNF395 and APP. The results were published in Nature (2014). We also published an invited editorial feature in Cell cycle journal based on this study. Our work was also highlighted by the editors at Nature Cancer Reviews.
Gene expression is highly regulated in order to achieve the requisite repertoire of RNA and protein products across the vast space of possible cellular phenotypes encompassing physiological and developmental contingencies. Five years ago, we embarked on a path to catalog the sequences in RNA that play substantial regulatory roles, by providing linear or structural information for
Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. The vast landscape of RNA regulatory elements remains largely uncharacterized. We recently described a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. TEISER (tool for eliciting informative structural elements in RNA), which marks our first successful attempt to reveal structural regulatory elements that underlie transcript stability in vivo was recently published. This study was published in the May 10th (2012) issue of Nature. TEISER can be downloaded here. A limited version has also been integrated into iGET for public use.