Grant: Project Grant

Our genes are encoded on large DNA molecules called chromosomes. Individual cells must compact their chromosomes in a unique way to silence genes not expressed while maintaining an open configuration for active genes. A neural progenitor cell will have many genes that are open or poised while it divides but once it commits to becoming a neuron many of these genes must be tightly packaged as they will not be required after differentiation. The cell manages this process with a complex series of proteins that control the structure of chromosomes and the regulation of genes. When this process is defective, cells cannot divide, differentiate or initiate gene expression effectively. Indeed, mutations affecting chromosome regulating proteins cause a variety of neurodevelopmental disability disorders, including mutations in the BPTF gene. Despite our success in identifying disease causing genes, how they coordinate which genes to turn on or off, when to turn them on or off, and in what order remains poorly defined. For BPTF, we know that it functions in a complex called NURF, that also includes a second remodeling protein called SMARCA1 or its close relative SMARCA5. With the previous grant we generated mice lacking the Smarca1 gene. The progenitors were delayed in their differentiation into neurons, thus making a larger brain. In contrast, deletion of the Smarca5 gene resulted in much smaller brains because the progenitors differentiated too quickly. Here, we postulated that the NURF complex controls the transition from progenitor to neuron and that it requires a switch in partners, from Smarca5 for progenitor growth to Smarca1 for differentiation. We will identify and confirm when and how a subunit switch occurs, and we will identify the genes that are affected by this switch. This data will provide valuable insight into the differentiation process, how genes become activated or repressed, and how this can cause intellectual disability.