Genomic imprinting does not reduce the dosage of UBE3A in neurons

BACKGROUND: 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 neurodevelopmen...

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Autores principales: Hillman, Paul R., Christian, Sarah G. B., Doan, Ryan, Cohen, Noah D., Konganti, Kranti, Douglas, Kory, Wang, Xu, Samollow, Paul B., Dindot, Scott V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433054/
https://www.ncbi.nlm.nih.gov/pubmed/28515788
http://dx.doi.org/10.1186/s13072-017-0134-4
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author Hillman, Paul R.
Christian, Sarah G. B.
Doan, Ryan
Cohen, Noah D.
Konganti, Kranti
Douglas, Kory
Wang, Xu
Samollow, Paul B.
Dindot, Scott V.
author_facet Hillman, Paul R.
Christian, Sarah G. B.
Doan, Ryan
Cohen, Noah D.
Konganti, Kranti
Douglas, Kory
Wang, Xu
Samollow, Paul B.
Dindot, Scott V.
author_sort Hillman, Paul R.
collection PubMed
description BACKGROUND: 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. 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. RESULTS: Overall, 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. CONCLUSIONS: Based 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 MATERIAL: The online version of this article (doi:10.1186/s13072-017-0134-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-54330542017-05-17 Genomic imprinting does not reduce the dosage of UBE3A in neurons Hillman, Paul R. Christian, Sarah G. B. Doan, Ryan Cohen, Noah D. Konganti, Kranti Douglas, Kory Wang, Xu Samollow, Paul B. Dindot, Scott V. Epigenetics Chromatin Research BACKGROUND: 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. 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. RESULTS: Overall, 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. CONCLUSIONS: Based 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 MATERIAL: The online version of this article (doi:10.1186/s13072-017-0134-4) contains supplementary material, which is available to authorized users. BioMed Central 2017-05-15 /pmc/articles/PMC5433054/ /pubmed/28515788 http://dx.doi.org/10.1186/s13072-017-0134-4 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Hillman, Paul R.
Christian, Sarah G. B.
Doan, Ryan
Cohen, Noah D.
Konganti, Kranti
Douglas, Kory
Wang, Xu
Samollow, Paul B.
Dindot, Scott V.
Genomic imprinting does not reduce the dosage of UBE3A in neurons
title Genomic imprinting does not reduce the dosage of UBE3A in neurons
title_full Genomic imprinting does not reduce the dosage of UBE3A in neurons
title_fullStr Genomic imprinting does not reduce the dosage of UBE3A in neurons
title_full_unstemmed Genomic imprinting does not reduce the dosage of UBE3A in neurons
title_short Genomic imprinting does not reduce the dosage of UBE3A in neurons
title_sort genomic imprinting does not reduce the dosage of ube3a in neurons
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433054/
https://www.ncbi.nlm.nih.gov/pubmed/28515788
http://dx.doi.org/10.1186/s13072-017-0134-4
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