A proliferation associated tRNA regulatory nexus on human chromosome 6 plays a central role in cell state-dependent gene expression

Redundancy in the genetic code provides robustness against mutations and errors in translation. It also allows cells to encode additional information within a coding sequence alongside the polypeptide chain itself. Here, we show that genes expressed in different cellular states employ distinct codon usage patterns linked to post-transcriptional regulation of protein expression. During proliferation, gene expression programmes favour codons ending in A or T, while in quiescence, genes are enriched for G or C ending codons. In parallel, the tRNA pool broadly shifts to match the differing codon demands in each state. Further, the majority of tRNA genes up regulated during proliferation are confined to a small, distinct locus on human chromosome 6. Together these findings reveal a striking and previously unreported regulatory programme that exploits redundancy in the genetic code to impose an additional layer of gene expression control, driven by a proliferation-associated tRNA regulatory nexus on chromosome 6.