Diagenode

Premature termination codons in the gene cause reduced local mRNA synthesis.


García-Rodríguez R, Hiller M, Jiménez-Gracia L, van der Pal Z, Balog J, Adamzek K, Aartsma-Rus A, Spitali P

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene leading to the presence of premature termination codons (PTC). Previous transcriptional studies have shown reduced DMD transcript levels in DMD patient and animal model muscles when PTC are present. Nonsense-mediated decay (NMD) has been suggested to be responsible for the observed reduction, but there is no experimental evidence supporting this claim. In this study, we aimed to investigate the mechanism responsible for the drop in expression levels in the presence of PTC. We observed that the inhibition of NMD does not normalize gene expression in DMD. Additionally, in situ hybridization showed that DMD messenger RNA primarily localizes in the nuclear compartment, confirming that a cytoplasmic mechanism like NMD indeed cannot be responsible for the observed reduction. Sequencing of nascent RNA to explore transcription dynamics revealed a lower rate of transcription in patient-derived myotubes compared to healthy controls, suggesting a transcriptional mechanism involved in reduced DMD transcript levels. Chromatin immunoprecipitation in muscle showed increased levels of the repressive histone mark H3K9me3 in mice compared to wild-type mice, indicating a chromatin conformation less prone to transcription in mice. In line with this finding, treatment with the histone deacetylase inhibitor givinostat caused a significant increase in DMD transcript expression in mice. Overall, our findings show that transcription dynamics across the locus are affected by the presence of PTC, hinting at a possible epigenetic mechanism responsible for this process.

Tags
Antibody

Share this article

Published
July, 2020

Source

Products used in this publication

  • ChIP-seq Grade
    C15410058
    H3K36me3 polyclonal antibody

イベント

  • IHEC Annual meeting 2022
    Quebec, Canada
    Oct 4-Oct 7, 2022
  • Danish RNA Society's 7th Annual Meeting on RNA
    Aarhus, Denmark
    Oct 11, 2022
  • ASHG 2022
    Los Angeles, California, USA
    Oct 25-Oct 29, 2022
  • International Conference on Epigenetics and Bioengineering 2022
    Houston, Texas, USA
    Oct 27-Oct 29, 2022
  • Long-Read Sequencing Meeting Uppsala LRUA22 Meeting
    Uppsala, Sweden
    Oct 31-Nov 2, 2022
  • Association for Molecular Pathology 2022
    Phoenix, Arizona, USA
    Nov 1-Nov 5, 2022
 すべてのイベントを見る

ニュース

 すべてのニュースを見る


The European Regional Development Fund and Wallonia are investing in your future.

Extension of industrial buildings and new laboratories.


       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy   |   Diagenode Diagnostics