Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

Hsien Sung Huang, John Allen, Angela M. Mabb, Ian F. King, Jayalakshmi Miriyala, Bonnie Taylor-Blake, Noah Sciaky, J. Walter Dutton, Hyeong Min Lee, Xin Chen, Jian Jin, Arlene S. Bridges, Mark J. Zylka, Bryan L. Roth, Benjamin D. Philpot

Research output: Contribution to journalArticle

197 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)185-191
Number of pages7
JournalNature
Volume481
Issue number7380
DOIs
StatePublished - Jan 12 2012
Externally publishedYes

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Topoisomerase Inhibitors
Topotecan
Ubiquitin-Protein Ligases
Alleles
Angelman Syndrome
Neurons
Dexrazoxane
irinotecan
Spinal Cord
Mothers
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Antisense RNA
Withholding Treatment
Sequence Deletion
Neocortex
Etoposide
Cerebellum
Nervous System
Hippocampus

ASJC Scopus subject areas

  • General

Cite this

Huang, H. S., Allen, J., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., ... Philpot, B. D. (2012). Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature, 481(7380), 185-191. https://doi.org/10.1038/nature10726

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. / Huang, Hsien Sung; Allen, John; 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.

In: Nature, Vol. 481, No. 7380, 12.01.2012, p. 185-191.

Research output: Contribution to journalArticle

Huang, HS, Allen, J, Mabb, AM, King, IF, Miriyala, J, Taylor-Blake, B, Sciaky, N, Dutton, JW, Lee, HM, Chen, X, Jin, J, Bridges, AS, Zylka, MJ, Roth, BL & Philpot, BD 2012, 'Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons', Nature, vol. 481, no. 7380, pp. 185-191. https://doi.org/10.1038/nature10726
Huang HS, Allen J, Mabb AM, King IF, Miriyala J, Taylor-Blake B et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2012 Jan 12;481(7380):185-191. https://doi.org/10.1038/nature10726
Huang, Hsien Sung ; Allen, John ; 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. / Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. In: Nature. 2012 ; Vol. 481, No. 7380. pp. 185-191.
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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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