An innovative approach to functionally study the effect of epigenetic modifications on stem cells, neural development and brain tumours.

• Applicant: Professor Dr. Stefan Stricker
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 257151303

Brain development is a highly complex process that relies on temporally and spatially defined changes in gene expression. Decades of thorough scientific experiments helped pinpointing the roles of hundreds of gene products in the control the self-renewal of pluri- and multipotent embryonic stem cells, the lineage decision into neural differentiation, self-renewal of neural stem cells and their differentiation into the three neural lineages. How these gene activities are established and inherited during neural development and how epigenetic mechanisms influence those is much less clear. One reason for this is the lack of experimental approaches that enable manipulation of epigenetic processes and subsequently testing the functional relevance of those during neural development or disease.Histone modifications are among the most commonly studied epigenetic marks. Many different histone modifications are known of which some specifically coincide with certain gene activities. Different modifications on the N-terminal tail of histone H3 for example correlate either with active or repressed gene activities. Interestingly, some of these modified sites are frequently mutated in pediatric brain or bone tumours showing that cells harbouring histone modifications are viable and despite global chromatin changes can have surprisingly specific phenotypic effects. Taken together these new insights make histone mutations an excellent tool to study epigenetic gene regulation in a relevant biological context. We have generated histone genes carrying mutations incompatible with certain posttranslational modifications and introduced those into neural and embryonic stem cells. This enables to functionally test the effect these mutations have on chromatin and transcription, self-renewal and differentiation of stem cells and analyze the consequences on brain development and (since histone mutations frequently occur in brain and bone tumour patients) on tumourigenicity. Our approach follows specific questions in experimental systems of our expertise, but refers to general issues of epigenetic gene regulation and could significantly help advancing our understanding of stem cell biology, neural development and disease.

• DFG Programme: Research Grants