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BIOLOGICAL SCIENCES: Genetics

View ORCID ProfileJack S. Hsiao, Noelle D. Germain, Andrea Wilderman, Christopher Stoddard, Luke A. Wojenski, Geno J. Villafano, Leighton Core, View ORCID ProfileJustin Cotney, View ORCID ProfileStormy J. Chamberlain
doi: https://doi.org/10.1101/404061
Jack S. Hsiao
Dept. of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403
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  • ORCID record for Jack S. Hsiao
Noelle D. Germain
Dept. of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403
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Andrea Wilderman
Dept. of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403
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Christopher Stoddard
Dept. of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403
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Luke A. Wojenski
Dept. of Molecular and Cellular Biology, University of Connecticut, Storrs, CT
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Geno J. Villafano
Dept. of Molecular and Cellular Biology, University of Connecticut, Storrs, CT
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Leighton Core
Dept. of Molecular and Cellular Biology, University of Connecticut, Storrs, CTInstitute for Systems Genomics, University of Connecticut, Storrs, CT
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Justin Cotney
Dept. of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403Institute for Systems Genomics, University of Connecticut, Storrs, CT
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Stormy J. Chamberlain
Dept. of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403Institute for Systems Genomics, University of Connecticut, Storrs, CT
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ABSTRACT

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 upregulation 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 upregulation of UBE3A-ATS. These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.

SIGNIFICANCE STATEMENT Angelman syndrome is a neurodevelopmental disorder caused by loss of function from the maternal allele of UBE3A, an imprinted gene. The paternal allele of UBE3A is silenced by a long, non-coding antisense transcript in mature neurons. We have identified a boundary element that stops the transcription of the antisense transcript in human pluripotent stem cells, and thus restricts UBE3A imprinted expression to neurons. We further determined that UBE3A imprinting requires both the loss of the boundary function and sufficient expression of the antisense transcript to silence paternal UBE3A. These findings provide essential details about the mechanisms of UBE3A imprinting that may suggest additional therapeutic approaches for Angelman syndrome.

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Posted August 31, 2018.
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BIOLOGICAL SCIENCES: Genetics
Jack S. Hsiao, Noelle D. Germain, Andrea Wilderman, Christopher Stoddard, Luke A. Wojenski, Geno J. Villafano, Leighton Core, Justin Cotney, Stormy J. Chamberlain
bioRxiv 404061; doi: https://doi.org/10.1101/404061
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BIOLOGICAL SCIENCES: Genetics
Jack S. Hsiao, Noelle D. Germain, Andrea Wilderman, Christopher Stoddard, Luke A. Wojenski, Geno J. Villafano, Leighton Core, Justin Cotney, Stormy J. Chamberlain
bioRxiv 404061; doi: https://doi.org/10.1101/404061

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