Genomic imprinting does not reduce the dosage of UBE3A in neurons

Abstract

BackgroundThe ubiquitin protein E3A ligase gene (UBE3A) gene is imprinted with maternal-specific expression in neurons and biallelically expressed in all other cell types. Both loss-of-function and gain-of-function mutations affecting the dosage of UBE3A are associated with several neurodevelopmental syndromes and psychological conditions, suggesting that UBE3A is dosage-sensitive in the brain. The observation that loss of imprinting increases the dosage of UBE3A in brain further suggests that inactivation of the paternal UBE3A allele evolved as a dosage-regulating mechanism. To test this hypothesis, we examined UBE3A transcript and protein levels among cells, tissues, and species with different imprinting states of UBE3A.ResultsOverall, we found no correlation between the imprinting status and dosage of UBE3A. Importantly, we found that maternal Ube3a protein levels increase in step with decreasing paternal Ube3a protein levels during neurogenesis in mouse, fully compensating for loss of expression of the paternal Ube3a allele in neurons.ConclusionsBased on our findings, we propose that imprinting of UBE3A does not function to reduce the dosage of UBE3A in neurons but rather to regulate some other, as yet unknown, aspect of gene expression or protein function.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-017-0134-4) contains supplementary material, which is available to authorized users.

Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders

“…For AS, mouse models have been used to implicate loss of UBE3A expression in the brain as the primary cause of specific deficits in AS 15 . However, few studies have been performed in human peripheral tissues 16 , 17 .…”

“…However, few studies have been performed in human peripheral tissues 16 , 17 . UBE3A is a key gene in neurodevelopment and is thought to be imprinted only in neurons, where it is expressed from the maternal allele in humans and mice 15 . Interestingly in other cell types UBE3A has bi-allelic expression 18 and is thought to be consistently expressed from both alleles in different peripheral tissues 15 .…”

“…UBE3A is a key gene in neurodevelopment and is thought to be imprinted only in neurons, where it is expressed from the maternal allele in humans and mice 15 . Interestingly in other cell types UBE3A has bi-allelic expression 18 and is thought to be consistently expressed from both alleles in different peripheral tissues 15 . The silencing of UBE3A on the paternal allele in neurons is thought to be regulated by a paternally expressed antisense transcript of UBE3A .…”

Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A

“…However, we could not observe paternal UBE3A silencing in neurotypical hCOs ( Figure 3B). This is expected as previous reports in mice showed that maternal UBE3A dosage compensates for paternal imprinting (Hillman et al, 2017). Therefore, to observe paternal UBE3A silencing we obtained a human induced pluripotent stem cell line previously generated from an Angelman syndrome patient (Chamberlain et al, 2010) and created hCOs from them (AS hCO).…”

An unbiased drug screen for seizure suppressors in Dup15q syndrome reveals 5HT1Aand dopamine pathway activation as potential therapies

“…Epilepsy is a common co-morbidity with ASD in general (15,(38)(39)(40)(41)(42)(43), but can be even more severe and difficult to treat in syndromic forms of ASD like Dup15q syndrome (1,16,44,45). In fact, most children with isodicentric duplications of 15q that include four copies of the UBE3A gene, presumably active in glia where it is not imprinted (18)(19)(20)(21), suffer from pharmacoresistant seizures (16). Here we utilized our fly model of Dup15q to screen for previously approved compounds that can suppress seizures due to elevated levels of UBE3A in glia, not neurons (17).…”