Investigating convergent gene expression and neuronal activity phenotypes in human and mouse neurons caused by depletion and mutation of mental disease-associated chromatin regulators

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Mental disorders, such as autism and schizophrenia, are highly prevalent and are a huge health burden. They can be diverse and have multifactorial genetic origins, yet they often result in overlapping cognitive, social and molecular phenotypes. While mutations in synaptic components can mechanistically explain impaired neuronal function in patients, emerging evidence highlights involvement of several chromatin regulators in mental disorders. However, the underlying molecular mechanisms by which mutations of chromatin regulators lead to mental disorders are poorly understood. In this proposal we aim to investigate the hypothesis that mutation of distinct chromatin regulators converge on common gene networks to contribute to mental disorders. We suggest that mutually dependent or overlapping regulation of genetic networks essential for neuronal development and function play a role in the convergence. Mechanistically this could be mediated either by regulating hierarchical cascades of gene regulatory networks independently and/or by protein-protein interactions amongst ubiquitously expressed chromatin factors present in most cell types and neuron specific transcription factors to converge on overlapping target genes. To elucidate these possibilities, we will combine stem cell-derived induced neuronal differentiation and primary mouse neurons with functional and molecular characterization. Combining human and mouse neurons allows a controlled and detailed study of the organization of chromatin, gene regulation and neuronal activity throughout the establishment of nerve cell identity and are therefore excellent models for studying how chromatin regulators can influence neuronal function and mental illness. Specifically, we will deplete or mutate selected chromatin regulators implicated in mental disorders and study their effect on neuronal differentiation, gene expression and electrophysiological function. In addition, we will analyze the protein-protein interaction networks and epigenetic effects of these chromatin regulators to understand their molecular mechanism of action. Ultimately, our work will provide new basic insights into the gene regulatory networks involved in mental disorders and explain the potential converging role of chromatin regulators and their biochemical networks in causing these diseases.