Remodeling and development of therapeutic strategies for disease causing structural variations affecting genome architecture

• Applicant: Dr. Katerina Kraft
• Subject Area: Human Genetics ; General Genetics and Functional Genome Biology ; Developmental Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 408367449

Precise spatiotemporal gene expression is important for normal organism development and maintenance and requires many layers of transcriptional regulation. At one level, cis-regulatory elements, termed enhancers, drive the cell-type and time specific expression of developmental genes. Distal enhancers confer their activity to genes via chromatin looping and this three dimensional chromatin structure constrains enhancer activity to the target genes. Disruptions in enhancer activity caused by genomic rearrangements, such as structural variations, can lead to disease. However, the precise outcome of structural variations is difficult to predict due to specific spatiotemporal gene expression, enhancer activity and genome architecture and therefore until now had to be tested in vivo. Furthermore it remains unclear whether specific 3D structures formed in various tissues contribute to or are merely consequences of gene expression. Here I will bypass these problems using catalytically inactive Cas9 in vitro in embryonic stem cells that carry structural variations and analyze the changes in chromatin architecture and gene expression that follow enhancer activation.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Howard Chang, Ph.D.