Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Estrogen receptor alpha (ERa) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERa on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERa coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERa largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERa depletion lack features which limit translation efficiency including structured 50 UTRs and miRNA target sites. In contrast, mRNAs induced upon ERa depletion whose polysome association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERa regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERadependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.