SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells
Menée sur des cellules de glioblastome humain, cette étude met en évidence un mécanisme par lequel la répression, induite par le facteur de transcription SOX4, de l'expression d'ARNs de transfert spécifiques inhibe la prolifération des cellules cancéreuses
Transfer RNAs (tRNAs) are essential for mRNA translation and protein synthesis. Their expression is tightly associated with cell states and is broadly controlled by the recruitment of Pol III through intragenic elements. Whether and how tRNA genes could also be individually regulated is not known. In this study, our results reveal that a polymerase II-dependent DNA-binding transcription factor can also regulate the expression of specific tRNAs through direct binding to DNA elements surrounding the tRNA genes. Such a regulatory mode may have broader implications into understanding how cells coordinate mRNA translation and codon usage with cell state and behavior, such as proliferation and reprogramming of human glioblastoma cells.Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAiMet. Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAiMet greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAiMet partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.