Research

The aim of our research is to develop an epigenetic therapy for the disease Prader-Willi syndrome (PWS). PWS is an epigenetic disorder that leads to the silencing of the expression of a group of genes on chromosome 15 (15q11-q13).

Each person has two sets of chromosomes, one set inherited from the father (paternal) and one set inherited from the mother (maternal). The combination of the two inherited variants usually results in the expression of both maternal and paternal genes and the transmission of genetic traits from both parents. However, there are rare sections of chromosomes where gene activity is regulated according to the maternal or paternal origin of the entire chromosome. This phenomenon is called genetic imprinting. The mechanism of genetic imprinting is not fully understood, but it results in the modification of DNA by methylation. Such DNA is inactive and the genes it encodes are not expressed. This is also the case for a stretch of DNA on chromosome 15 (15q11-q13), which is active only on the paternal chromosome, while genes on the maternally inherited chromosome are silenced.

Thus, people with PWS completely lose the ability to express genes in the affected region (PWS locus) of the paternal chromosome, either due to loss of part of the chromosome (deletion on the paternal chromosome) or by accidental replacement with a maternally inactivated sequence (uniparental disomy). Even though PWS patients lack expression of important genes, potentially functional copies of these genes are still stored on the maternal chromosome, but are inactive due to DNA methylation.

The goal of our supported research is to selectively reactivate gene expression from the PWS locus on the maternal chromosome by manipulating molecular epigenetic factors and ideally achieve durable therapeutic outcomes for PWS patients.