Journal article

Translational offsetting as a mode of estrogen receptor alpha-dependent regulation of gene expression

Julie Lorent, Eric P Kusnadi, Vincent van Hoef, Richard J Rebello, Matthew Leibovitch, Johannes Ristau, Shan Chen, Mitchell G Lawrence, Krzysztof J Szkop, Baila Samreen, Preetika Balanathan, Francesca Rapino, Pierre Close, Patricia Bukczynska, Karin Scharmann, Itsuhiro Takizawa, Gail P Risbridger, Luke A Selth, Sebastian A Leidel, Qishan Lin Show all

The EMBO Journal | WILEY | Published : 2019

Abstract

Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα 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 ERα de..

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Grants

Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Department of Health and Human Services acting through the Victorian Cancer Agency


Awarded by DFG


Awarded by Canadian Institutes for Health Research


Awarded by National Institutes of Health


Awarded by Joint Canada-Israel Health Research Program (JCIHRP)


Awarded by Fonds de Recherche du Quebec-Sante


Funding Acknowledgements

The authors acknowledge A. Hanson and G. Laven-Law for expert technical assistance with ChIP-qPCR, A. Puri for technical assistance with Western blots, and Dr. T. Begley for advice with tRNA modification analysis. The authors would like to acknowledge support from Science for Life Laboratory, the National Genomics Infrastructure (NGI) and Bioinformatics and Expression Analysis (BEA, Karolinska Institutet) core facilities and Uppmax for providing assistance in massive parallel sequencing, DNA microarray processing and computational infrastructure. The research was supported by the Swedish Research Council, the Wallenberg Academy Fellow Program, the Swedish Cancer Society, the Cancer Society in Stockholm and STRATCAN (to OL); National Health and Medical Research Council (NHMRC) grants APP1141339 to ITo, OL, LF; APP 1102752 to GPR and APP 1145777 to LAS; the Department of Health and Human Services acting through the Victorian Cancer Agency (MCRF16007) to LF and (MCRF18017) to MGL; EJ Whitten Foundation to LF; DFG grant [LE 3260/3-1] to SAL; Walloon Excellence in Life Sciences and Biotechnology (WELBIO) to PC; Canadian Institutes for Health Research (MOP-363027) and National Institutes of Health grants (R01 CA 202021-01-A1) (to ITo); Joint Canada-Israel Health Research Program (JCIHRP) (108589-001) (to ITo and OL). ITo is supported by Junior 2 award from Fonds de Recherche du Quebec-Sante (34872). This project was further facilitated by funding from the Swedish foundation for international cooperation in research and higher education (STINT) to ITo, OL, and LF.