Evidence for an Integrated Gene Repression Mechanism Based on MRNA Isoform Toggling in Human Cells

Overview

Journal G3 (Bethesda)

Publisher Oxford University Press

Specialties Genetics
Molecular Biology

Date 2019 Feb 7

PMID 30723103

Citations 18

Authors

Ina Hollerer

Juliet C Barker

Victoria Jorgensen

Amy Tresenrider

Claire Dugast-Darzacq

Leon Y Chan

Xavier Darzacq

Robert Tjian

Elcin Unal

Gloria A Brar

Affiliations

Soon will be listed here.

Abstract

We recently described an unconventional mode of gene regulation in budding yeast by which transcriptional and translational interference collaborate to down-regulate protein expression. Developmentally timed transcriptional interference inhibited production of a well translated mRNA isoform and resulted in the production of an mRNA isoform containing inhibitory upstream open reading frames (uORFs) that prevented translation of the main ORF. Transcriptional interference and uORF-based translational repression are established mechanisms outside of yeast, but whether this type of regulation was conserved was unknown. Here we find that, indeed, a similar type of regulation occurs at the locus for the human oncogene We observe evidence of transcriptional interference between the two promoters, which produce a poorly translated distal promoter-derived uORF-containing mRNA isoform and a well-translated proximal promoter-derived transcript. Down-regulation of distal promoter activity markedly proximal promoter-driven expression and results in local reduction of histone H3K36 trimethylation. Moreover, we observe that this transcript toggling between the two isoforms naturally occurs during human embryonic stem cell differentiation programs.

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