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Evidence for an Integrated Gene Repression Mechanism based on mRNA Isoform Toggling in Human Cells

By Ina Hollerer, Juliet C Barker, Victoria Jorgensen, Amy Tresenrider, Claire Dugast-Darzacq, Leon Y. Chan, Xavier Darzacq, Robert Tjian, Elçin Ünal, Gloria A Brar

Posted 13 Feb 2018
bioRxiv DOI: 10.1101/264721 (published DOI: 10.1534/g3.118.200802)

We recently discovered a common mode of gene regulation in budding yeast, by which mRNA production represses protein expression. Whether this regulatory mechanism is conserved was unknown. Here we find that a similar mechanism regulates the human oncogene MDM2, which is transcribed from two promoters. Transcription from the distal MDM2 promoter produces a poorly translated mRNA isoform and transcription from the proximal promoter produces a well-translated transcript. Remarkably, we find that down-regulation of transcription from the distal promoter markedly up-regulates expression from the proximal promoter and results in the loss of histone H3K36 trimethylation marks. Moreover, we observe transcript toggling between the two different MDM2 isoforms as a natural part of two distinct human embryonic stem cell differentiation programs. We conclude that the integrated gene repression mechanism recently identified in yeast is conserved in human cells.

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