Genetic & Epigenetic Pathways of Disease

Genetic & Epigenetic Pathways of Disease

To achieve our mission, members of the genetic and epigenetic subtheme are engaged in technology development. These range from single molecule studies of reconstituted model chromatin through elucidation of epigenetic marks on a genome wide level and the implementation of Next Generation Sequencing (NGS) in fundamental research as well as in a diagnostic setting. Important lines of research focus on the molecular and cellular aspects of tumorgenic pathways, development and function of the nervous system, and the basic mechanisms of including epigenetics. Epigenetic marks such as DNA methylation and histone modifications mark genomic regions for transcriptional activity or repression. The role of many epigenetic modifications in health and disease remains elusive. These epigenetic mechanisms are studied in the context of mammalian hematopoietic and embryonic stem cells, yeast, parasites (plasmodium) and vertebrate embryos (Xenopus). Another goal is to uncover the molecular pathways and processes that underlie normal functioning of the central nervous system (CNS; e.g. mental retardation, intellectual disability, autism, schizophrenia and brain tumours) and the neuro-sensory system (blindness, deafness). Cell-specific transgenic approaches are used to elucidate the roles of proteins of unknown function and to examine the (epi)genetic basis of neurodevelopmental psychopathological disorders. Another important topic is the study protein networks in ciliary structures that are disrupted in various heritable forms of blindness, deafness and combined deaf-blindness (Usher syndrome). Proteins have been identified in a protein network in photoreceptors that localizes to the transition zone of the ciliary axoneme of these cells, the connecting cilium. In addition, subsets of the network have been identified at the cilia of tissues, affected in associated phenotypes, like kidney, brain and inner ear. Finally, genetic and epigenetic research on intellectual disabilities makes extensive use of model organisms such as the mouse and especially the fruit flyDrosophila melanogasterto study neuropathological defects and to elucidate disrupted molecular and cellular processes. Created fly models for intellectual disability are developed for use in screens to identify genetic modifiers and small molecule drugs that can modulate the mutant phenotype with the ultimate goal to develop strategies for therapy. In oncology rapid developments in targeted therapy enable the introduction of findings from basic genomic research into clinical application, both for diagnostics and for disease definition. Especially in lymphoma and colorectal cancer this has led to pioneering work.

Theme leader: Hans van Bokhoven