Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons
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 o...
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| Published in | Nature (London) Vol. 481; no. 7380; pp. 185 - 189 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
21.12.2011
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0028-0836 1476-4687 1476-4687 |
| DOI | 10.1038/nature10726 |
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| Abstract | 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. |
|---|---|
| AbstractList | 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 12weeks 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. 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 silenced 4 – 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 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 Ube3a 9 – 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. 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.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. 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. 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. |
| Author | Jin, Jian Bridges, Arlene S. Huang, Hsien-Sung Zylka, Mark J. Dutton, J. Walter Lee, Hyeong-Min Philpot, Benjamin D. Miriyala, Jayalakshmi Taylor-Blake, Bonnie Chen, Xin Mabb, Angela M. Sciaky, Noah Roth, Bryan L. Allen, John A. King, Ian F. |
| AuthorAffiliation | 1 Department of Cell and Molecular Physiology, University of North Carolina (UNC) at Chapel Hill, School of Medicine 7 UNC Neuroscience Center 3 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy 4 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy 8 National Institute of Mental Health, Psychoactive Drug Screening Program 2 Department of Pharmacology, UNC School of Medicine 5 Department of Pathology and Laboratory Medicine, UNC School of Medicine 6 UNC Carolina Institute for Developmental Disabilities |
| AuthorAffiliation_xml | – name: 4 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy – name: 3 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy – name: 1 Department of Cell and Molecular Physiology, University of North Carolina (UNC) at Chapel Hill, School of Medicine – name: 7 UNC Neuroscience Center – name: 6 UNC Carolina Institute for Developmental Disabilities – name: 2 Department of Pharmacology, UNC School of Medicine – name: 5 Department of Pathology and Laboratory Medicine, UNC School of Medicine – name: 8 National Institute of Mental Health, Psychoactive Drug Screening Program |
| Author_xml | – sequence: 1 givenname: Hsien-Sung surname: Huang fullname: Huang, Hsien-Sung organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine – sequence: 2 givenname: John A. surname: Allen fullname: Allen, John A. organization: Department of Pharmacology, University of North Carolina School of Medicine – sequence: 3 givenname: Angela M. surname: Mabb fullname: Mabb, Angela M. organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine – sequence: 4 givenname: Ian F. surname: King fullname: King, Ian F. organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine – sequence: 5 givenname: Jayalakshmi surname: Miriyala fullname: Miriyala, Jayalakshmi organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine – sequence: 6 givenname: Bonnie surname: Taylor-Blake fullname: Taylor-Blake, Bonnie organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine – sequence: 7 givenname: Noah surname: Sciaky fullname: Sciaky, Noah organization: Department of Pharmacology, University of North Carolina School of Medicine – sequence: 8 givenname: J. Walter surname: Dutton fullname: Dutton, J. Walter organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine – sequence: 9 givenname: Hyeong-Min surname: Lee fullname: Lee, Hyeong-Min organization: Department of Pharmacology, University of North Carolina School of Medicine – sequence: 10 givenname: Xin surname: Chen fullname: Chen, Xin organization: Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy – sequence: 11 givenname: Jian surname: Jin fullname: Jin, Jian organization: Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy – sequence: 12 givenname: Arlene S. surname: Bridges fullname: Bridges, Arlene S. organization: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine – sequence: 13 givenname: Mark J. surname: Zylka fullname: Zylka, Mark J. email: zylka@med.unc.edu organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Carolina Institute for Developmental Disabilities, University of North Carolina, University of North Carolina Neuroscience Center – sequence: 14 givenname: Bryan L. surname: Roth fullname: Roth, Bryan L. email: bryan_roth@med.unc.edu organization: Department of Pharmacology, University of North Carolina School of Medicine, Carolina Institute for Developmental Disabilities, University of North Carolina, University of North Carolina Neuroscience Center, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, Department of Pharmacology, National Institute of Mental Health, Psychoactive Drug Screening Program, University of North Carolina School of Medicine – sequence: 15 givenname: Benjamin D. surname: Philpot fullname: Philpot, Benjamin D. email: bphilpot@med.unc.edu organization: Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Carolina Institute for Developmental Disabilities, University of North Carolina, University of North Carolina Neuroscience Center |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22190039$$D View this record in MEDLINE/PubMed |
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| Snippet | Cancer drugs that can potentially treat Angelman syndrome are identified.
Angelman syndrome mutation reversed
Genomic imprinting disorders arise owing to a... Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In... Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A ( Ube3a ) 1... |
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| SubjectTerms | 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 |
| Title | Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons |
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