Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons
Open accessAbstract
Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify 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 Ube3a. These results indicate 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 12 weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Although 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.
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Maternal deletion of a single imprinted, maternally expressed gene encoding UBE3A on 15q11-q13 gives rise to the Angelman syndrome phenotype.
“Similarly, paternal-specific deletion of multiple imprinted, paternally expressed genes on the 15q11–q13 region results in Prader–Willi syndrome, whereas maternal deletion of a single, imprinted, maternally expressed gene encoding a ubiquitin-protein ligase (UBE3A) on this same region gives rise to the Angelman syndrome phenotype.”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [193]
Using an unbiased screen in primary cortical neurons from mice, Huang et al. identified several topoisomerase inhibitors that unsilence the paternal allele of UBE3A.
“Using an unbiased screen in primary cortical neurons from mice, Huang et al. 101 identified several topoisomerase inhibitors that unsilence the paternal allele of UBE3A”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [101]
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- Authors
- Huang, H.-S., Allen, J. A., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. W., Lee, H.-M., Chen, X., Jin, J., Bridges, A. S., Zylka, M. J., Roth, B. L., & Philpot, B. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Zylka, Mark J.
- Roth, Bryan L.
- Philpot, Benjamin D.
- ORCID
- Venue
- Nature
- Published
- 2011-12-21
- Volume
- 481
- Issue
- 7380
- Pages
- 185-189
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3257422
- OpenAlex
- W2016365513
- Cited by
- 387
- References
- 38
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 18 · 2023: 18 · 2022: 17 · 2021: 15 · 2020: 34 · 2019: 24 · 2018: 22 · 2017: 33 · 2016: 37 · 2015: 34 · 2014: 38 · 2013: 35 · 2012: 26
- FWCI
- 20.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Public Health Service (HHSN-271-2008-00025-C)
- National Institute of Mental Health (R01MH093372)
- National Eye Institute (R01EY018323)
- National Institute of Neurological Disorders and Stroke (R01NS060725, R01NS067688, P30NS045892, F32NS067712)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30-HD03110, P30HD003110, T32HD040127)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Angelman syndrome, UBE3A, genomic imprinting, topoisomerase inhibitors, topotecan, epigenetic silencing, antisense RNA, cortical neurons, irinotecan, etoposide, dexrazoxane, drug repurposing, long-term drug effects
- MeSH terms
- Alleles, Animals, Cells, Cultured, Cerebral Cortex, Drug Evaluation, Preclinical, Fathers, Female, Male, Mice, Inbred C57BL, Mothers, Neurons, Angelman Syndrome, Genomic Imprinting, Topotecan, Gene Silencing, Ubiquitin-Protein Ligases, Mice, Small Molecule Libraries, Topoisomerase Inhibitors
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