Angelman Syndrome, a Genomic Imprinting Disorder of the Brain

Chamberlain, Stormy J.; Lalande, Marc

doi:10.1523/jneurosci.1728-10.2010

Cited by 102 publications

(78 citation statements)

References 57 publications

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“…Expression of this antisense transcript leads to silencing of the Ube3a gene, whose loss-of-function has been characterized as the fundamental genetic basis for Angelman syndrome (AS) [91]. Topotecan was recently identified as an AS candidate drug for its inhibition of Ube3a-ATS and restoration of Ube3a expression in mouse neurons and brain [92].…”

Section: R-loops and Antisense Transcriptionmentioning

confidence: 99%

R-loop: an emerging regulator of chromatin dynamics

Al-Hadid

Yang

2016

ABBS

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The dynamic structure of chromatin, which exists in two conformational states: heterochromatin and euchromatin, alters the accessibility of the DNA to regulatory factors during transcription, replication, recombination, and DNA damage repair. Chemical modifications of histones and DNA, as well as adenosine triphospahate-dependent nucleosome remodeling, have been the major focus of research on chromatin dynamics over the past two decades. However, recent studies using a DNA-RNA hybrid-specific antibody and next-generation sequencing approaches have revealed that the formation of R-loops, one of the most common non-canonical DNA structures, is an emerging regulator of chromatin states. This review focuses on recent insights into the interplay between R-loop formation and the epigenetic modifications of chromatin in normal and disease states.

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Section: R-loops and Antisense Transcriptionmentioning

confidence: 99%

R-loop: an emerging regulator of chromatin dynamics

Al-Hadid

Yang

2016

ABBS

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“…AS and PWS are both characterized by hypotonia at birth, disordered sleep, autistic features, and intellectual disabilities, but the diseases differentiate into phenotypically distinct syndromes in early childhood (1,2). Seizures, ataxia, and inappropriate laughter characterize AS, whereas hyperphagia leading to obesity and obsessive-compulsive behaviors characterize PWS.…”

mentioning

confidence: 99%

R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation

Powell

Coulson

Gonzales

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

138

129

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Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are oppositely imprinted autism-spectrum disorders with known genetic bases, but complex epigenetic mechanisms underlie their pathogenesis. The PWS/AS locus on 15q11-q13 is regulated by an imprinting control region that is maternally methylated and silenced. The PWS imprinting control region is the promoter for a one megabase paternal transcript encoding the ubiquitous protein-coding Snrpn gene and multiple neuron-specific noncoding RNAs, including the PWS-related Snord116 repetitive locus of small nucleolar RNAs and host genes, and the antisense transcript to AScausing ubiquitin ligase encoding Ube3a (Ube3a-ATS). Neuronspecific transcriptional progression through Ube3a-ATS correlates with paternal Ube3a silencing and chromatin decondensation. Interestingly, topoisomerase inhibitors, including topotecan, were recently identified in an unbiased drug screen for compounds that could reverse the silent paternal allele of Ube3a in neurons, but the mechanism of topotecan action on the PWS/AS locus is unknown. Here, we demonstrate that topotecan treatment stabilizes the formation of RNA:DNA hybrids (R loops) at G-skewed repeat elements within paternal Snord116, corresponding to increased chromatin decondensation and inhibition of Ube3a-ATS expression. Neural precursor cells from paternal Snord116 deletion mice exhibit increased Ube3a-ATS levels in differentiated neurons and show a reduced effect of topotecan compared with wild-type neurons. These results demonstrate that the AS candidate drug topotecan acts predominantly through stabilizing R loops and chromatin decondensation at the paternally expressed PWS Snord116 locus. Our study holds promise for targeted therapies to the Snord116 locus for both AS and PWS.rader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinted neurodevelopmental disorders caused by oppositely inherited deficiencies of chromosome 15q11-q13. AS and PWS are both characterized by hypotonia at birth, disordered sleep, autistic features, and intellectual disabilities, but the diseases differentiate into phenotypically distinct syndromes in early childhood (1, 2). Seizures, ataxia, and inappropriate laughter characterize AS, whereas hyperphagia leading to obesity and obsessive-compulsive behaviors characterize PWS. Maternal mutations in UBE3A/Ube3a in humans and mice have identified the loss of function of this ubiquitin E3 ligase encoding gene as the cause of AS (3, 4). For PWS, small deletions of the HBII-85/ SNORD116 locus (5-7) and two mouse models of Snord116 deletions (8, 9) have identified the minimal causative deficiency to be the paternally expressed, highly repetitive, long noncoding RNA (lncRNA) that is processed into multiple small nucleolar RNAs (snoRNAs) and spliced nuclear retained host genes (116HG and 115HG) (10,11).A recent drug screen discovered that topoisomerase inhibitors, including topotecan, reduce Ube3a-ATS by an unknown mechanism to reverse the silencing of paternal Ube3a in mouse neurons and brain (12). Topotec...

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“…UBE3A encodes the E3 ubiquitin ligase Ube3a, this gene is epigenetically imprinted throughout neuronal brain cells (Chamberlain and Lalande 2010). Ube3a attaches ubiquitin to diverse substrates and modifies the function and/or the turn-over of the ubiquitinylated proteins among which are a certain number of Golgi proteins.…”

Section: E3 Ubiquitin Ligasementioning

confidence: 99%

Golgi post‐translational modifications and associated diseases

Potelle

Klein

Foulquier

2015

J of Inher Metab Disea

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For non specialists, Golgi is a very well known subcellular compartment involved in secretion and correct targeting of soluble and transmembrane proteins. Nevertheless, Golgi is also specifically involved in many different and diverse post-translational modifications. Through its diverse functions, Golgi is not only able to modify secreted and transmembrane proteins but also cytoplasmic proteins. The Golgi apparatus research field is so broad that an exhaustive review of this organelle is not doable here. The goal of this review is to cover the main post-translational modifications occurring at the Golgi level and present the identified associated diseases.

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Angelman Syndrome, a Genomic Imprinting Disorder of the Brain

Cited by 102 publications

References 57 publications

R-loop: an emerging regulator of chromatin dynamics

R-loop: an emerging regulator of chromatin dynamics

R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation

Golgi post‐translational modifications and associated diseases

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