Determinants of the stability of DNA methylation changes

Epigenetic processes determine how cells acquire, maintain and read memories of past events (information imprints). A key question in epigenetics is if, and to what extent, information imprints are maintained and determine future cellular phenotypes. This is crucial for distinguishing those that are functional, from those that mark prior events but are inconsequential for future responses. We therefore propose a reappraisal of the epigenome as a mark of cellular history. We focus on DNA methylation as it has a long half-life and is thus well suited for long-term information storage. The central goal of this research project is to understand if and how DNA methylation changes can affect disease risk in the long term. Through in-depth genomic and bioinformatics analyses as well as state-of-the-art functional epigenetic screens, we will study the genomic contexts in which DNA methylation changes are stably maintained in vitro. We will also assess such changes in patients in 2 disease contexts: cancer, and intra-uterine growth restriction because of placental insufficiency. Ultimately, we aim to provide a framework to evaluate if and how local DNA methylation changes cause long-term effects, and to discriminate which of the plethora of DNA methylation changes detected in many diseases, contribute to the phenotype. As epigenetic alterations are reversible and druggable, this distinction is critical and has direct therapeutic consequences.