Decreasing UBE3A levels has a profound effect on the expression of multiple other genes, mostly due to chemical modifications in the DNA, a new study found. The research shows that loss of UBE3A-affected genes were associated with autism, decreased motor and cognitive activity, and energy expenditure, providing a new link between UBE3A and the symptoms experienced by those with Angelman syndrome.
Interestingly, researchers also found that altering UBE3A levels affected the expression of more than half of known imprinted genes without changing the underlying DNA sequence.
The study, “UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons,” was published in the journal Epigenetics.
Abnormal gene expression in neurodevelopmental disorders is a complex process involving not only genes, but other molecular mechanisms as well.
UBE3A gene loss leads to many of the characteristic features of Angelman syndrome. Usually, people inherit one UBE3A copy from each parent and both copies are turned on in various body tissues. However, only the copy inherited from the mother is active in some brain areas.
Disease occurs when the maternal UBE3A disappears from a person’s genome, or when it suffers any mutation, as he or she will no longer have active UBE3A copies in the neurons.
This parent-specific gene activation phenomenon is known as genomic imprinting and UBE3A is an imprinted gene.
Genome imprinting is related to DNA methylation. Simply put, it is a molecular mechanism that has the ability to change DNA activity without altering its structure (sequence). The mechanism involves the addition of chemicals, called methyl groups, into the DNA sequence. If a DNA sequence is highly methylated, chances are the machinery won’t be able to reach the DNA, read the sequence, and produce proteins from it.
Additionally, UBE3A encodes a ubiquitin E3 ligase protein, a protein involved in protein degradation, which has many molecular targets.
To understand the impact of neuronal UBE3A levels on DNA methylation and gene expression, researchers inactivated the UBE3A gene in two human neuronal cell culture models.
Results show that UBE3A loss led to differentially methylated regions (DMRs) in genes involved in brain development and gene expression. Also, researchers found that decreasing UBE3A levels altered the methylation of up to half of known imprinted genes. This suggests a key role for UBE3A in a neuronal imprinted gene network.
“DMR analysis revealed genes involved in brain morphology and synaptic vesicle activity as well as genes implicated in autism spectrum disorder relevant physiologic deficits including broad face, waddling gait,” the team added.
Together, the team’s work revealed some interesting insights into the diseases caused by altered UBE3A levels, and most importantly, it revealed for the first time the existence of an UBE3A-mediated imprinted gene network in neurons.