Determining TADs as conserved regulatory units in vertebrate heart development
How the information for complex spatiotemporal gene expression patterns is encoded in the genome remains a fundamental question in biology. Major advances in recent years have highlighted the importance of the 3D chromatin structure for gene regulation and identified topologically associating domains (TADs) as conserved spatial units of the genome. Interestingly, TADs overlap with gene regulatory landscapes and large syntenic blocks, raising the possibility that these domains reflect a conserved functional unit of the genome. This poses the question whether TADs are able to function independently of their genome of origin. Here, I propose to study the relationship between conserved TADs and gene regulation using vertebrate heart development as a model system. The hearts of birds and mammals share many general features but have evolved independently over the past 250 million years. I will study the conservation of gene regulatory mechanims in vertebrate heart development by comparing 3D-chromatin architecture and epigenetic landscapes in chicken and mouse heart development. In a second phase, I will take this comparison one step further and experimentally test the functional conservation of TADs. Using a combination of genome engineering and BAC-transgenesis, I will insert entire chicken TADs into the mouse genome. I will then test if and how the 3D-chromatin architecture, epigenetic landscapes, and ultimately the biological output of the transgenic chicken TADs produce a transgene that is functional in the exogenous genome. The results of this study will elucidate to which degree DNA sequence determines chromatin folding and how homologous regulatory landscapes are able to fold and function if transplanted into species separated by over 250 million years of evolution.
Dr. Daniel Murad Ibrahim,Berlin
Charité – Universitätsmedizin Berlin
Berlin-Brandenburger Centrum für Regenerative Therapien