Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons
Public Deposited- Creator
- Huang, Hsien-Sung
- Allen, John A.
- Mabb, Angela M.
- King, Ian F.
- Miriyala, Jayalakshmi
- Taylor-Blake, Bonnie
- Sciaky, Noah
- Dutton, J. Walter
- Lee, Hyeong-Min
- Chen, Xin
- Jin, Jian
- Bridges, Arlene S.
- Zylka, Mark J.
- Roth, Bryan L.
- Philpot, Benjamin D.
- Abstract
- Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (Ube3a)1–3. In neurons, the paternal allele of Ube3a is intact but epigenetically silenced4–6, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein7,8. Using an unbiased, high-content screen in primary cortical neurons from mice, we identified twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide, and dexrazoxane (ICRF-187). At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a9–11. These results suggest that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least twelve weeks after cessation of topotecan treatment, suggesting transient topoisomerase inhibition can have enduring effects on gene expression. While potential off-target effects remain to be investigated, our findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome.
- Date of publication
- 2012
- Keyword
- Allèle
- Enzyme
- Pathologie du système nerveux central
- Nervous system diseases
- Inhibiteur enzyme
- Complex syndrome
- Cerebral disorder
- Central nervous system disease
- Pathologie du système nerveux
- Carbon-nitrogen ligases
- Allele
- Happy puppet syndrome
- Malformation
- Mouse
- Rodentia
- Syndrome happy puppet
- Mammalia
- Enzyme inhibitor
- Ligases
- Souris
- Neurone
- Vertebrata
- Neuron
- Ubiquitin-protein ligase
- Congenital disease
- DOI
- Identifier
- Publisher DOI: https://doi.org/10.1038/nature10726
- PMCID: PMC3257422
- PMID: 22190039
- Onescience id: 0df400dea473e90687c8a2b78a0223fa8ef8d78a
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- Nature
- Journal volume
- 481
- Journal issue
- 7380
- Page start
- 185
- Page end
- 189
- Language
- English
- ISSN
- 0028-0836
- 1476-4687
- 0302-2889
Relations
- Parents:
This work has no parents.
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