Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders

Abstract

The E3 ubiquitin ligase UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies.

Keywords: Angelman syndrome; Dup15q syndrome; imprinting; neurodevelopment; proteosome; ubiquitin.

Figure 1.. Parent of origin expression patterns of the 15q11.2–q13.3 disorders.

The chromosomal abnormalities leading to copy number changes of UBE3A are diagrammed, with maternal chromosomes in red and paternal chromosomes in blue and the UBE3A copies represented as yellow bands. Specific genetic subtypes of Prader–Willi syndrome and Angelman syndrome are indicated. For Prader–Willi syndrome, these include deletion (˜75%), maternal uniparental disomy (˜25%) and imprinting defect (˜1%). For Angelman syndrome, these include deletion (˜75%), paternal uniparental disomy (˜2%), imprinting defect (˜2%) and UBE3A mutation (˜20%). Due to parental imprinting, the paternal copy of UBE3A is repressed in postnatal neurons, so the number of expressed copies of UBE3A is shown for each genetic disorder in the left table. ID: Imprinting defects; Mat: Maternal; MatUPD: Maternal uniparental disomy; Pat: Paternal.

Figure 2.. UBE3A mutations observed in Angelman syndrome.

The genetic locations of Angelman syndrome mutations are mapped relative to the HECT domain encoding E3 ligase function (green bar) and the encoding exons of UBE3A. Alternatively spliced exons 1–8 are shown in dark grey, consistent exons are in light grey and alternative exons due to polyadenylation differences are hatched grey. Current numbering of exons was according to [50]. HECT: Homologous to E6AP C-terminus.

Figure 3.. Imprinting and neuron-specific epigenetic regulation of UBE3A.

The CpG sites of both maternal and paternal alleles of UBE3A are unmethylated (open circles), resulting in biallelic transcription of the 5′ end of UBE3A (arrows pointed left, exons represented as vertical bars). However, the Prader–Willi imprinting control region (PWS-ICR, in blue) is characterized by DNA methylation (closed circles) and repressive chromatin marks on the maternal allele (pink box) and active chromatin marks on the paternal allele (blue box). The Angelman imprinting control region (AS-ICR, pink) is characterized by paternal-specific DNA methylation because the maternal allele is protected from methylation at this region by the oocyte-specific transcription of noncoding upstream exons that serve to methylate the PWS-ICR on the maternal allele. While paternal expression of the protein coding gene SNRPN is observed in all tissues, transcriptional progression continues in postnatal neurons through the repetitive small nucleolar RNA clusters through to the antisense transcript for UBE3A (UBE3A-ATS). Specifically in neurons, the paternal allele undergoes chromatin decondensation and the maternal allele of UBE3A is silenced from expression of the UBE3A-ATS. AS-ICR: Angelman syndrome imprinting control region; PWS-ICR: Prader–Willi syndrome imprinting control region.