PROJECT SUMMARY Collective data from recent whole exome sequencing studies in schizophrenia confirmed a prominent enrichment of gene-disruptive de novo loss-of-function mutations and led to the identification of the contribution of SETD1A, which encodes for a histone methyltransferase. Notably, SETD1A mutations confer a large increase in disease risk, which provides a good starting point for disease modeling. Unambiguous identification of SETD1A as a SCZ risk gene emphasizes the important role that neural gene regulation plays in the genetic architecture of schizophrenia, consistent with accumulating evidence supporting an important role of regulatory common and rare variants in neuropsychiatric disease risk. This finding is also consistent with several lines of evidence suggesting that histone methylation is more broadly relevant to SCZ including the recent observation that histone methylation showed the strongest statistical enrichment among 4,939 biological pathways in GWAS data of psychiatric disorders. The fact that both common and rare risk variants aggregate in this particular biological pathway highlights its importance for the etiology of schizophrenia. However it is not clear at this stage how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease- specific insight. In this regard, the SETD1A finding provides a handle, a starting point from which to build a model and test hypotheses. The goal of this proposal is to address the critical question of how chromatin regulation deficits play a role in the pathogenesis of SCZ by (i) investigating the developmental requirement of Setd1a on cognitive and synaptic function in mice and the nature of the neural circuits affected by its deficiency (ii) identifying direct neuronal targets of Setd1a in the prefrontal cortex and (iii) generating and analyzing human SETD1A-deficient cortical neurons. The ultimate goal of the proposed studies of chromatin regulation in mental illness is to understand when/where/how genetic vulnerabilities affect gene expression in the brain and shape brain circuitry and function. The proposed studies will also reveal a host of schizophrenia candidate genes and promise important advances in our understanding, diagnosis, and treatment of debilitating psychiatric disorders, such as schizophrenia.