mRNA expression-mediated gene repression in human cells

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.