Journal
G3-GENES GENOMES GENETICS
Volume 9, Issue 4, Pages 1045-1053Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/g3.118.200802
Keywords
gene expression regulation; MDM2; LUTI; transcript isoform; uORF translation
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Funding
- Pew Charitable Trusts [00027344, 00029624]
- Damon Runyon Cancer Research Foundation [35-15]
- National Institutes of Health [DP2 AG055946-01, DP2 GM-119138]
- Glenn Foundation for Medical Research
- Alfred P. Sloan Foundation [FG-2016-6229]
- California Institute of Regenerative Medicine (CIRM) [LA1-08013]
- Howard Hughes Medical Institute [003061]
- Shurl and Kay Curci Foundation
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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 integrated regulation was conserved was unknown. Here we find that, indeed, a similar type of regulation occurs at the locus for the human oncogene MDM2. We observe evidence of transcriptional interference between the two MDM2 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 up-regulates proximal promoter-driven expression and results in local reduction of histone H3K36 trimethylation. Moreover, we observe that this transcript toggling between the two MDM2 isoforms naturally occurs during human embryonic stem cell differentiation programs.
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