PT  - JOURNAL ARTICLE
AU  - Ina Hollerer
AU  - Juliet C. Barker
AU  - Victoria Jorgensen
AU  - Amy Tresenrider
AU  - Claire Dugast-Darzacq
AU  - Leon Y. Chan
AU  - Xavier Darzacq
AU  - Robert Tjian
AU  - Elçin Ünal
AU  - Gloria A. Brar
TI  - mRNA expression-mediated gene repression in human cells
AID  - 10.1101/264721
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 264721
4099  - http://biorxiv.org/content/early/2018/02/13/264721.short
4100  - http://biorxiv.org/content/early/2018/02/13/264721.full
AB  - We previously discovered a new mode of gene regulation in budding yeast, by which mRNA production represses protein expression through a cis-acting transcriptional and translational interference mechanism (Chen et al., 2017; Chia et al., 2017). Whether this regulatory mechanism is conserved in other eukaryotes was unknown. Here we found that a similar mechanism regulates the human oncogene MDM2, which is transcribed from two different promoters. Transcription from the distal MDM2 promoter produces a poorly translated mRNA isoform, which establishes repressive histone H3K36 trimethylation marks at the proximal MDM2 promoter. In this manner, production of the 5’-extended transcript interferes with the expression of the MDM2 transcripts that are well translated. Accordingly, downregulation of transcription from the distal promoter up-regulates MDM2 protein levels. We conclude that this non-canonical mechanism, first defined in yeast, is conserved in human cells. We propose that a similar mechanism may modulate the expression of other mammalian genes with alternative promoters and differentially translated mRNA isoforms.