Spatial Genome Architecture in Development & Disease

Cell-state specific 3D genome architecture in heterogeneous cell populations of the brain


Accurate levels of gene expression during development and in environmental responses are mediated through specific three-dimensional (3D) contacts between non-coding regulatory regions and their target genes. Defects in the spatial relationship of regulatory elements to their target genes are linked to disease, and are increasingly important to understand complex neurological disorders, often associated with deregulation of chromatin factors. However, efforts to study 4D genome architecture in the nervous system have been limited to the use of bulk tissues, cells differentiated in vitro or neurons dissociated from the brain. Thus, it remains a major challenge to dissect the 4D nucleome alterations that accompany activation processes in specific neurons, and how they relate with homeostatic responses during neuronal activation and in circadian processes.  In this proposal, we aim to understand the relationship between the 4D genome and gene expression in specific cells of the brain, and its deregulation in neurodevelopmental disorders associated with Shank3 mutations, which are risk factors for Autism Spectrum Disorders (ASD). Further to its synaptic roles, Shank3 shuttles to the nucleus where it modulates gene expression in response to neuronal activity. First, we will determine 3D genome topologies in specialized pyramidal neurons in the hippocampus of wildtype and mutant Shank3 mice, to investigate Shank3 genomic targets and mechanisms of action. Second, we will develop a novel technology to dissect quantitative relationships between 3D folding patterns and cellular levels of nuclear factors, an essential step towards finer dissection of 3D genome folding mechanisms in heterogeneous tissues such as the brain.