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

Autor: Ina Hollerer, Elçin Ünal, Gloria A. Brar, Leon Y. Chan, Claire Dugast-Darzacq, Robert Tjian, Xavier Darzacq, Amy Tresenrider, Juliet C Barker, Victoria Jorgensen
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Gene isoform
Chromatin Immunoprecipitation
1.1 Normal biological development and functioning
QH426-470
Investigations
Promoter Regions
Histones
03 medical and health sciences
0302 clinical medicine
Genetic
MDM2
Stem Cell Research - Nonembryonic - Human
Underpinning research
Transcription (biology)
Models
transcript isoform
Genetics
Humans
uORF translation
Promoter Regions
Genetic
Molecular Biology
Genetics (clinical)
030304 developmental biology
Regulation of gene expression
0303 health sciences
Messenger RNA
biology
Models
Genetic
Promoter
Proto-Oncogene Proteins c-mdm2
gene expression regulation
Stem Cell Research
Embryonic stem cell
Cell biology
Open reading frame
Histone
LUTI
Gene Knockdown Techniques
biology.protein
MCF-7 Cells
Mdm2
CRISPR-Cas Systems
030217 neurology & neurosurgery
Biotechnology
Zdroj: G3: Genes|Genomes|Genetics
G3: Genes, Genomes, Genetics, Vol 9, Iss 4, Pp 1045-1053 (2019)
G3 (Bethesda, Md.), vol 9, iss 4
Hollerer, Ina; Barker, Juliet C; Jorgensen, Victoria; Tresenrider, Amy; Dugast-Darzacq, Claire; Chan, Leon Y; et al.(2019). Evidence for an Integrated Gene Repression Mechanism Based on mRNA Isoform Toggling in Human Cells.. G3 (Bethesda, Md.), g3.200802.2018-g3.200802.2018. doi: 10.1534/g3.118.200802. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/4nq7v2gj
DOI: 10.1101/264721
Popis: 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.
Databáze: OpenAIRE
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