Epigenetic mechanisms are fundamental to the normal development of multicellular organisms. DNA methylation and histone modifications are the two main mediators of epigenetic regulationa, and these marks allow cells to “remember”, which genes should be switched on or off. Not surprisingly, errors in epigenetic state “epimutations” can result in altered gene expression, compromised cell function and disease. But much remains unknown about the mechanisms, by which epigenetic patterns are established and maintained. The question that inspires us, is to understand how mutations in factors that read, write or erase epigenetic marks lead to human disease, with the ultimate aim to develop targeted epigenetic therapies.
Towards this goal, we are making use of a unique set of models that emerged from a large chemical mutagenesis screen for epigenetic regulators in the mouse. This screen identified about 30 unique genes, Modifiers of murine metastable epialleles Dominant (MommeD), with roles in DNA methylation, histone modification and chromatin remodelling pathways. Intriguingly, many of these factors have also been identified as risk factors for human disease. With this knowledge, we are selecting key factors as entry points into understanding their functions throughout normal development and in disease.
For instance, in the context of Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome, we aim to elucidate how mutations in four different genes can lead to a primary immunodeficiency characterized by hypo- or agammaglobulinemia and DNA hypomethylation of repetitive DNA. Our recent work established the first direct link between the ICF genes ZBTB24 and CDCA7. We are also investigating the transcriptional and epigenetic networks orchestrating immune cell development and function, using chromatin profiling (collaboration with Prof Frank Staal, IHB).
To tackle these challenges, we employ discovery-driven (epi)genomic approaches to expose epigenetic dysregulation, caused by disruption of our genes of interest, in model systems and patient-derived cells in combination with hypothesis-driven genetics, biochemistry, molecular biology and Crispr/Cas9-mediated (epi)genome-editing studies to systematically unravel the underlying molecular processes and identify disease-relevant endogenous targets.