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Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression
Author(s) -
Lorent Julie,
Kusnadi Eric P,
Hoef Vincent,
Rebello Richard J,
Leibovitch Matthew,
Ristau Johannes,
Chen Shan,
Lawrence Mitchell G,
Szkop Krzysztof J,
Samreen Baila,
Balanathan Preetika,
Rapino Francesca,
Close Pierre,
Bukczynska Patricia,
Scharmann Karin,
Takizawa Itsuhiro,
Risbridger Gail P,
Selth Luke A,
Leidel Sebastian A,
Lin Qishan,
Topisirovic Ivan,
Larsson Ola,
Furic Luc
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018101323
Subject(s) - biology , gene expression , gene , estrogen receptor , regulation of gene expression , genetics , microbiology and biotechnology , translational regulation , computational biology , messenger rna , translation (biology) , cancer , breast cancer
Estrogen receptor alpha ( ER α) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ER α on cancer‐associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ER α coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ER α largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNA s and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ER α depletion lack features which limit translation efficiency including structured 5′ UTR s and mi RNA target sites. In contrast, mRNA s induced upon ER α depletion whose polysome association remains unaltered are enriched in codons requiring U34‐modified tRNA s for efficient decoding. Consistently, ER α regulates levels of U34‐modifying enzymes and thereby controls levels of U34‐modified tRNA s. These findings unravel a hitherto unprecedented mechanism of ER α‐dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone‐dependent cancers.