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

Ina Hollerer, Juliet C. Barker, Victoria Jorgensen, Amy Tresenrider, Claire Dugast-Darzacq, View ORCID ProfileLeon Y. Chan, View ORCID ProfileXavier Darzacq, View ORCID ProfileRobert Tjian, View ORCID ProfileElçin Ünal, Gloria A. Brar
doi: https://doi.org/10.1101/264721
Ina Hollerer
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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Juliet C. Barker
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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Victoria Jorgensen
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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Amy Tresenrider
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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Claire Dugast-Darzacq
2Department of Molecular and Cell Biology, Li Ka Shing Center, University of California, Berkeley, CA, USA, 94720
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Leon Y. Chan
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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  • ORCID record for Leon Y. Chan
Xavier Darzacq
2Department of Molecular and Cell Biology, Li Ka Shing Center, University of California, Berkeley, CA, USA, 94720
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Robert Tjian
2Department of Molecular and Cell Biology, Li Ka Shing Center, University of California, Berkeley, CA, USA, 94720
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Elçin Ünal
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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  • ORCID record for Elçin Ünal
  • For correspondence: gabrar@berkeley.edu elcin@berkeley.edu
Gloria A. Brar
1Department of Molecular and Cell Biology, Barker Hall, University of California, Berkeley, CA, USA, 94720
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  • For correspondence: gabrar@berkeley.edu elcin@berkeley.edu
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ABSTRACT

We recently described an unconventional mode of gene regulation in budding yeast by which transcriptional and translational interference were used in an integrated manner 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 blocked translation of the 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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  • ↵3 Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA, 02139

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Posted October 05, 2018.
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Evidence for an Integrated Gene Repression Mechanism Based on mRNA Isoform Toggling in Human Cells
Ina Hollerer, Juliet C. Barker, Victoria Jorgensen, Amy Tresenrider, Claire Dugast-Darzacq, Leon Y. Chan, Xavier Darzacq, Robert Tjian, Elçin Ünal, Gloria A. Brar
bioRxiv 264721; doi: https://doi.org/10.1101/264721
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Evidence for an Integrated Gene Repression Mechanism Based on mRNA Isoform Toggling in Human Cells
Ina Hollerer, Juliet C. Barker, Victoria Jorgensen, Amy Tresenrider, Claire Dugast-Darzacq, Leon Y. Chan, Xavier Darzacq, Robert Tjian, Elçin Ünal, Gloria A. Brar
bioRxiv 264721; doi: https://doi.org/10.1101/264721

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