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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
10:06

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in

Anthony R Dallosso1, Anne L Hancock, Sally Malik

  • 1CLIC Sargent Research Unit, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.

RNA (New York, N.Y.)
|October 18, 2007
PubMed

Insights

Antisense RNAs (WT1-AS) regulate the WT1 gene, crucial for development and implicated in cancers like Wilms tumor and AML. These RNAs interact with WT1 mRNA, and their dysregulation contributes to malignancy.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Biology

Background:

  • Antisense RNAs are prevalent but poorly understood in mammals.
  • The WT1 gene is vital for development and linked to Wilms tumor (WT) and acute myeloid leukemia (AML).
  • WT1-AS, an antisense transcript of WT1, was previously shown to regulate WT1 protein levels.

Purpose of the Study:

  • To investigate the function and regulation of WT1 antisense RNA (WT1-AS).
  • To explore the role of WT1-AS in normal development and its potential involvement in WT and AML.

Main Methods:

  • Analysis of WT1-AS spliceoforms in human and mouse tissues.
  • Correlation of WT1-AS expression with DNA methylation of the antisense regulatory region (ARR).
  • Investigation of WT1-AS localization and interaction with WT1 mRNA using heteroduplex formation assays.

Main Results:

  • WT1-AS exists in multiple spliceoforms, co-expressed with WT1 RNA.
  • WT1-AS expression correlates with ARR methylation, showing imprinted monoallelic expression in normal kidney but loss of imprinting in WT.
  • WT1-AS localizes to the cytoplasm, forms heteroduplexes with WT1 mRNA, and exhibits abnormal splicing in AML.

Conclusions:

  • WT1 encodes conserved antisense RNAs (WT1-AS) that regulate WT1 expression through RNA:RNA interactions.
  • WT1-AS plays a conserved regulatory role in WT1 expression.
  • Deregulation of WT1-AS, including abnormal splicing in AML, contributes to cancer development.

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