Skip to main content
European Commission logo print header

Functions and mechanism of active DNA demethylation

Final Report Summary - DNADEMETHYLASE (Functions and mechanism of active DNA demethylation)

Epigenetics is one of the major themes of modern genetics. Epigenetics describes mechanisms and consequences of hereditary chromosomal modifications that are not based on changes in the DNA sequence. One main epigenetic modifications concerns DNA bases whereby a chemical modification in form of methyl groups is attached to Cytosine, a basic building block of DNA to generate 5-methylcytosine (m5C). In DNA of animals, m5C is a common epigenetic mark associated with shutting genes off. DNA methylation plays important roles in gene expression, genomic imprinting, X chromosome inactivation, genomic instability, embryonic development and cancer. It has is become clear that DNA methylation is a dynamic process, which can be reversed by an enzymatic demethylation process. However, little is known about it.
Our research has contributed to unravelling this process by studying the role of the tumor suppressor gene Gadd45, a key regulator of DNA demethylation. We have provided evidence that Gadd45 acts as an adapter between genes to be demethylated and the enzymatic machinery carrying out the demethylation. Other central questions regarding Gadd45, which were addressed in the course of this ERC funded project were: What is the biological role of Gadd45? How is Gadd45 targeted to specific sites in the genome? One surprising finding in the course of the ERC funded project was that Gadd45g plays a critical role in mammalian sex determination, because genetically male mice mutant for Gadd45g develop as females. Another surprise was that ribonucleic acids act as a zip code to deliver Gadd45 and hence demethylation to a specific locus. Thus, thanks to ERC support we were able to further unravel the function and biological role of a key player involved in epigenetic regulation.