Genomic imprinting does not reduce the dosage of UBE3A in neurons

Paul R Hillman,Paul B Samollow,Kory Douglas,Scott V Dindot,Ryan Doan,Noah D Cohen,Kranti Konganti,Sarah G B Christian,Xu Wang

doi:10.1186/s13072-017-0134-4

Paul R Hillman, Paul B Samollow + Show 7 more

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https://doi.org/10.1186/s13072-017-0134-4

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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.

Highlights

The ubiquitin protein E3A ligase gene (UBE3A) gene is imprinted with maternal-specific expression in neurons and biallelically expressed in all other cell types
Ube3a/UBE3A is highly expressed from the maternal allele in the central nervous system (CNS) To determine whether imprinting of Ube3a in neurons of the mouse CNS reduces the dosage of Ube3a relative to other tissues where Ube3a is biallelically expressed, we compared the steady-state levels of Ube3a RNA and Ube3a protein among tissues in adult wild-type mice
Neither Ube3a RNA or Ube3a protein levels were significantly different in the CNS of Ube3am+/p+ and Ube3am+/p− mice (RNA: t = 0.9, p = 0.8; protein: CNS, t = 2.1, p = 0.2), indicating that the relatively high level of Ube3a expression in mouse CNS is primarily attributable to expression of the maternal allele

Summary

Introduction

The 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. Genomic imprinting is a rare epigenetic phenomenon that leads to the differential expression of paternally and maternally derived alleles of a gene in a parent-of-origin dependent manner [50, 54] It has been documented only in therian mammals and flowering plants and only at a few loci in mammals, of which fewer than half are imprinted in both mouse and human [1, 4, 8, 39, 42, 50, 52]. In both mouse and human, expression of Ube3aAS/UBE3A-AS in cis is both necessary and sufficient to silence expression of the paternal Ube3a/UBE3A allele [ [31], [33] ], which, at least in mouse, appears to occur by inhibiting transcriptional elongation, giving rise to a paternally expressed, 5′-truncated transcript of unknown function [33, 38]

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