Lab Journal club: tuning tRNA levels to control gene expression

In a recent lab journal club we discussed a recent paper from the Pilpel and Lund labs:

A dual program for translation regulation in cellular proliferation and differentiation.Gingold H, Tehler D, Christoffersen NR, Nielsen MM … Dahan O, Pedersen JS, Lund AH, Pilpel Y.  Cell 2014 Sep 11; 158(6):1281-92

Transfer RNAs (tRNAs) are essential for mRNA translation. However, tRNA synthesis is often considered merely a ‘house-keeping’ function. Moreover, a role for tRNA synthesis as a regulatory step for protein synthesis is largely ignored because it is assumed tRNA levels are maintained in excess. However, recent studies suggest otherwise: our lab showed that in Drosophila, elevated tRNA synthesis – and increased tRNAiMet in particular – can increase mRNA translation, drive tissue and body growth, and accelerate development (Rideout et al, 2012, PNAS). In addition, the lab of Tao Pan (Pavon-Eternod et al RNA 2013 Apr; 19(4):461-6) showed that increased tRNAiMet can promote proliferation in cultured mammalian epithelial cells.

In this wonderful paper from the Pilpel and Lund labs, the authors describe even more intricate links between tRNA and translation. They use tRNA microarray analysis of multiple cell types to, first, show that the relative levels of tRNAs within the total pool change depending on proliferative vs. differentiated status of cells, and, second, that these differences in tRNA expression patterns match predicted mRNA codon usage in the types of gene expressed in proliferating vs. differentiating cells. The paper contains many other striking observations, including those that may explain these selective tRNA expression changes and those that point to the widespread nature of the correlation between tRNA and codon usage. But, together, these data suggest the intriguing hypothesis that cells alter their tRNA expression patterns to match changes in codon usage in their mRNA transcriptomes.