Journal Article

A bipartite boundary element restricts UBE3A imprinting to mature neurons

Wilderman, Andrea, Chamberlain, Stormy J., Core, Leighton, Hsiao, Jack S., Cotney, Justin, Villafano, Geno J., Germain, Noelle D., Stoddard, Christopher, Wojenski, Luke A.

2019

Overview

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript (UBE3A-ATS) from the paternally inherited allele, which silences the paternal allele of UBE3A in cis. However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of UBE3A-ATS in humans. Removal of this element led to up-regulation of UBE3A-ATS without repressing paternal UBE3A. However, increasing expression of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A, demonstrating that UBE3A imprinting requires both the loss of function from the boundary element as well as the up-regulation of UBE3A-ATS. These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.

• Publisher: National Academy of Sciences
• Subject: Alleles / Angelman Syndrome - genetics / Antisense therapy / Binding Sites / Biological Sciences / Boundary element method / Chromatin - genetics / Chromatin - metabolism / CRISPR / Epistasis, Genetic / Exons / Gene Expression / Gene Expression Regulation / Genetics / Genomic Imprinting / Induced Pluripotent Stem Cells - cytology / Induced Pluripotent Stem Cells - metabolism / Mathematical analysis / Neurodevelopmental disorders / Neurons / Neurons - metabolism / Protein Binding / RNA, Antisense / RNA, Long Noncoding / Sequence Deletion / Transcription / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics