Topoisomerases facilitate transcription of long genes linked to autism

King, Ian; Yandava, Chandri; Mabb, Angela M.; Hsiao, Jack S.; Huang, Hsien-Sung; Pearson, Brandon L.; Calabrese, J. Mauro; Starmer, Joshua; Parker, Joel S.; Magnuson, Terry; Chamberlain, Stormy J.; Philpot, Benjamin D.; Zylka, Mark J.

doi:10.1038/nature12504

Cited by 370 publications

(493 citation statements)

References 47 publications

Supporting

Mentioning

450

Contrasting

Unclassified

Order By: Relevance

“…Several groups have attempted to reactivate the silenced paternal copy of Ube3a [74][75][76]. Large-scale small compound screening led to identification of the topoisomerase inhibitor topotecan as having the potential to activate Ube3a from the paternal allele [74,76,77].…”

Section: Research and Developmentmentioning

confidence: 99%

“…While details of topotecan's action remain to be elucidated, recent studies suggest that topotecan works by reducing the levels of Ube3a-ATS, thereby unsilencing the paternal allele of Ube3a. This may be accomplished through inhibition of topoisomerases, which relieves the torsional stress that results from the transcription of large transcripts thus blocking the production of the Ube3a-ATS or by stabilizing R-loops, or RNA-DNA hybrids, resulting in chromatin decondensation and Ube3a-ATS silencing [76,77]. Another approach used antisense oligonucleotides to interfere with the Ube3a-ATS transcript, which mediates the silencing of the paternal allele [75].…”

Section: Research and Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Angelman Syndrome

et al. 2015

View full text Add to dashboard Cite

In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

show abstract

Section: Research and Developmentmentioning

confidence: 99%

Section: Research and Developmentmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

View full text Add to dashboard Cite

show abstract

“…These observations are in good accordance with the finding that treatment of cells with topoisomerase I inhibitor elicits a redistribution of RNA polymerase along transcribed genes and enhances the escape from pausing sites. 40,49,50 This suggests that the pauserelease of the transcriptional machinery may be influenced by the specific DNA supercoiling balance at promoters. The precise mechanism still remains to be established, however one might hypothesize that the activity of pauseregulated factors and/or the processivity of transcriptional machinery are coupled to local DNA topology around the pause site.…”

Section: Dna Topology and Initiation Of Transcriptionmentioning

confidence: 99%

DNA topology and transcription

Kouzine¹,

Levens²,

Baranello³

2014

Nucleus

View full text Add to dashboard Cite

Chromatin is a complex assembly that compacts DNA inside the nucleus while providing the necessary level of accessibility to regulatory factors conscripted by cellular signaling systems. In this superstructure, DNA is the subject of mechanical forces applied by variety of molecular motors. Rather than being a rigid stick, DNA possesses dynamic structural variability that could be harnessed during critical steps of genome functioning. The strong relationship between DNA structure and key genomic processes necessitates the study of physical constrains acting on the double helix. Here we provide insight into the source, dynamics, and biology of DNA topological domains in the eukaryotic cells and summarize their possible involvement in gene transcription. We emphasize recent studies that might inspire and impact future experiments on the involvement of DNA topology in cellular functions.

show abstract

“…Top1 is a transcription factor for genes with especially long transcripts. Its inhibition reduces excitatory and inhibitory neurotransmission by depleting synaptic proteins (King, Yandava, Mabb, Hsiao, Huang, Pearson, Calabrese, Starmer, Parker, Magnuson, Chamberlain, Philpot, and Zylka, 2013;Mabb, Kullmann, Twomey, Miriyala, Philpot, and Zylka, 2014). Fkb1a is an immunophilin that binds to immunosuppressant drugs such as FK506 and rapamycin thereby modulating the mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

Hertler

Buitrago

Luft

et al. 2016

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

Motor learning is associated with plastic reorganization of neural networks in primary motor cortex (M1) that depends on changes in gene expression. Here, we investigate the temporal profile of these changes during motor memory formation in response to a skilled reaching task in rats. mRNA-levels were measured 1h, 7h and 24h after the end of a training session using microarray technique. To assure learning specificity, trained animals were compared to a control group. In response to motor learning, genes are sequentially regulated with high time-point specificity and a shift from initial suppression to later activation. The majority of regulated genes can be linked to learning-related plasticity. In the gene-expression cascade following motor learning, three different steps can be defined: (1) an initial suppression of genes influencing gene transcription. (2) Expression of genes that support translation of mRNA in defined compartments. (3) Expression of genes that immediately mediates plastic changes. Gene expression peaks after 24h -this is a much slower time-course when compared to hippocampusdependent learning, where peaks of gene-expression can be observed 6-12h after training ended. AbstractMotor learning is associated with plastic reorganization of neural networks in primary motor cortex (M1) that depends on changes in gene expression. Here, we investigate the temporal profile of these changes during motor memory formation in response to a skilled reaching task in rats. mRNA-levels were measured 1h, 7h and 24h after the end of a training session using microarray technique. To assure learning specificity, trained animals were compared to a control group. In response to motor learning, genes are sequentially regulated with high time-point specificity and a shift from initial suppression to later activation. The majority of regulated genes can be linked to learning-related plasticity. In the gene-expression cascade following motor learning, three different steps can be defined: 1) an initial suppression of genes influencing gene transcription. 2) Expression of genes that support translation of mRNA in defined compartments. 3) Expression of genes that immediately mediates plastic changes. Gene expression peaks after 24 hours -this is a much slower time-course when compared to hippocampus-dependent learning, where peaks of geneexpression can be observed 6 to 12 hours after training ended.3

show abstract

Topoisomerases facilitate transcription of long genes linked to autism

Cited by 370 publications

References 47 publications

Angelman Syndrome

Angelman Syndrome

DNA topology and transcription

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

Contact Info

Product

Resources

About