Manipulation of the mechanism that controls UBE3A gene activation status in the brain may represent an alternative strategy to treat Angelman syndrome, a study suggests.
The study, “A bipartite boundary element restricts UBE3A imprinting to mature neurons,” was published in the journal PNAS.
Humans inherit two active copies of each gene, one from the mother and one from the father. Usually both copies of each gene are active, or “turned on,” but for a small number of genes, only one of the copies is working, depending on which family member it was inherited from, and the other is turned off permanently. This phenomenon, called genomic imprinting, is tightly regulated, as activation of both copies can result in developmental and neurological disorders.
Expression of UBE3A from the copy inherited from the mother is essential in some regions of the brain, and its abnormal function or loss causes the neurodevelopmental symptoms associated with Angelman syndrome. About three percent of individuals with Angelman syndrome have an imprinting defect of the maternal copy, while the paternally inherited copy is silenced in the brain.
The silencing of parental UBE3A expression in neurons is caused by the production of a specific molecule called UBE3A-ATS. This molecule is known as an antisense transcript, a single stranded RNA molecule that is complementary to a protein coding messenger RNA with which it “interwinds,” thereby blocking its translation into protein (DNA is transformed into messenger RNA, and subsequently into a protein in a process called translation).
Understanding in detail how UBE3A-ATS works and how parental UBE3A could be re-activated may provide valuable clues for therapeutic interventions for Angelman syndrome.
A team led by researchers at UConn Health used the CRISPR/Cas9-mediated genome editing tool to explore the role of UBE3A-ATS in the silencing of UBE3A in Angelman syndrome. CRISPR/Cas9 allows scientists to edit an organism’s genome at any desired location.
By genetically editing the UBE3A-ATS sequence in human induced pluripotent stem cells collected from Angelman syndrome patients, the team could identify an element containing two parts that was essential to regulate the production of UBE3A-ATS in brain cells. iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of almost any type of human cell.
Removal of this element led to the overproduction of UBE3A-ATS without repressing paternal UBE3A. However, increasing levels of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A. These findings suggest “that UBE3A imprinting requires both the loss of function from the boundary element and the sufficient (amount) of (UBE3A-ATS) to silence paternal UBE3A,” the researchers wrote.
Therefore, manipulation of the competitive mechanism between UBE3A-ATS and UBE3A may “provide a potential therapeutic approach for Angelman syndrome,” the team suggests.