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Using the E1A Minigene Tool to Study mRNA Splicing Changes
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Regulatory mechanisms of incomplete huntingtin mRNA splicing

Andreas Neueder1,2, Anaelle A Dumas3, Agnesska C Benjamin3

  • 1UCL Huntington's Disease Centre, Department of Neurodegenerative Disease and Dementia Research Institute, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK. andreas.neueder@uni-ulm.de.

Nature Communications
|September 29, 2018
PubMed

Insights

Incomplete splicing of the HTT gene produces a pathogenic protein in Huntington's disease. Splicing factor SRSF6 and transcription speed influence this aberrant splicing event.

Area of Science:

  • Genetics
  • Molecular Biology
  • Neurodegenerative Diseases

Background:

  • Huntington's disease (HD) results from CAG repeat expansion in the HTT gene.
  • Aberrant splicing can produce a pathogenic HTT exon 1 protein (HTTexon1), but the mechanisms are unclear.

Purpose of the Study:

  • To investigate the mechanisms underlying HTTexon1 production.
  • To identify regulatory elements and factors involved in this splicing event.

Main Methods:

  • Development of a minigene system to study HTT splicing.
  • Analysis of intron 1 regions critical for incomplete splicing.
  • Investigation of splicing factor SRSF6 and RNA polymerase II transcription speed.

Main Results:

  • The minigene system recapitulated CAG repeat-length-dependent HTTexon1 production.
  • Specific regions of intron 1 were identified as necessary for incomplete splicing.
  • SRSF6 expression levels modulated HTTexon1 production, and transcription speed regulated its levels.

Conclusions:

  • Splicing factor SRSF6 and RNA polymerase II transcription speed are key regulators of pathogenic HTTexon1 production.
  • Understanding these mechanisms may lead to strategies for preventing HTT exon 1 protein generation in Huntington's disease.

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