Cited by 391Genetic Syndromes and ImprintingGenetics and Neurodevelopmental DisordersEpigenetics and DNA Methylation

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Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

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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.·2012·Nature

DOI 10.1038/nature10726PMC PMC3257422

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Abstract

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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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: Huang, Hsien-Sung
Allen, John A.
Mabb, Angela M.
King, Ian F.
Miriyala, Jayalakshmi
Lee, Hyeong-Min
Chen, Xin
Jin, Jian
Zylka, Mark J.
Roth, Bryan L.
Philpot, Benjamin D.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-12-21
Volume: 481
Issue: 7380
Pages: 185-189
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10726
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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Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

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