Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons

• Published in: Nature (London) Vol. 481; no. 7380; pp. 185 - 189
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.12.2011
• Subjects: 631/154/309/436; 631/208/200; 631/378/2571/1696; 692/699/375/366; Alleles; Angelman Syndrome - drug therapy; Angelman Syndrome - genetics; Animals; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Drug Evaluation, Preclinical; Fathers; Female; Gene Silencing - drug effects; Genomic Imprinting - drug effects; Genomic Imprinting - genetics; Humanities and Social Sciences; letter; Male; Mice; Mice, Inbred C57BL; Mothers; multidisciplinary; Neurons - drug effects; Neurons - metabolism; Science; Science (multidisciplinary); Small Molecule Libraries - administration & dosage; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Topoisomerase Inhibitors - administration & dosage; Topoisomerase Inhibitors - analysis; Topoisomerase Inhibitors - pharmacokinetics; Topoisomerase Inhibitors - pharmacology; Topotecan - administration & dosage; Topotecan - pharmacokinetics; Topotecan - pharmacology; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10726

Cancer drugs that can potentially treat Angelman syndrome are identified. Angelman syndrome mutation reversed Genomic imprinting disorders arise owing to a loss of function of non-imprinted alleles expressed from one parent. In Angelman syndrome, a neurodevelopmental disorder caused by dysfunction of the maternal allele of the Ube3a gene, the paternal allele remains intact but is epigenetically silenced. Benjamin Philpot and colleagues perform an unbiased drug screen on mouse cortical neurons expressing fluorescent Ube3a and identify topoisomerase inhibitors that are capable of activating paternal Ube3a , including topotecan, a cancer therapeutic approved by the US Food and Drug Administration. When the drug is delivered in vivo , paternal Ube3a is activated in multiple regions of the brain, and effects persist for several weeks after drug cessation. This demonstrates a potential method for reactivating dormant alleles of imprinted genes, which may be a therapeutic strategy in disorders such as Angelman syndrome. Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A ( UBE3A ) 1 , 2 , 3 . In neurons, the paternal allele of UBE3A is intact but epigenetically silenced 4 , 5 , 6 , raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein 7 , 8 . 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 9 , 10 , 11 . 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.