Title: Deciphering the Link between the Schizophrenia-risk Gene SETD1A and Activity-dependent Transcription
Description: Schizophrenia is a disabling psychiatric and neurodevelopmental disorder that represents a tremendous public health burden. Despite the inroads made in the treatment of its symptoms, understanding its etiology and pathophysiology remains challenging due to the genetic heterogeneity of the disease and the corresponding complexity of the neural systems which it affects. In recent years, the development of next generation sequencing and substantial progress in the field of psychiatric genetics have revealed the important role of individually rare but collectively common heritable and de novo mutations (DNMs) in the complex genetic architecture of schizophrenia. Previously, we had identified SETD1A encoding a histone methyltransferase, as a high-risk gene for schizophrenia, which has been confirmed extensively through follow-up meta-analyses. This discovery emphasized the important role that neural gene regulation plays in the coordination of complex cognitive processes. However, it is unclear how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease-specific insight.

Our previous comprehensive analysis of mutant mice carrying a loss of function (LoF) allele in the Setd1a orthologue uncovered the role of SETD1A in gene regulation, neuronal architecture, synaptic plasticity, neuronal ensemble activity and cognitive function and showed that neurocognitive deficits that derive from Setd1a deficiency can be reversed by pharmacological interventions during adulthood. Our previous ChIP-Seq analysis showed a striking overlap between SETD1A, MEF2, and LSD1 targets at enhancers in the prefrontal cortex (PFC). Since MEF2 is an activity dependent transcription factor, we hypothesized that SETD1A may also modulate activity-dependent gene expression in the brain. To elucidate the effects of Setd1a deficiency on activity-dependent transcription, we established an in vitro neuronal activity dependent gene (ADG) expression assay and identified genes modulated by neuronal activity using ChIP-Seq and RNA-Seq assays. We found a remarkable overlap of a dynamic pattern of activity-dependent recruitment of SETD1A, LSD1 and MEF2 to enhancers of ADGs.

Our results showed Setd1a deficiency affects transcription in an activity-dependent manner and transcriptional alteration induced by Setd1a deficiency under neuronal activation can be attenuated by inhibition of LSD1 activity. In addition, we investigated how SETD1A modulates MEF2 transactivation activity by performing luciferase assays. Our results suggest that SETD1A represses MEF2 activity but the repression is unlikely to be mediated by lysine methylation. We also performed behavioral analyses of Setd1a+/- mice and found that the social behavior and social memory were impaired in female Setd1a+/- mice but remained intact in male Setd1a+/- mice. Ultimately, future work is underway to analyze the targets of SETD1A, which in turn could lead to the development of therapeutic strategies to reverse the progression of schizophrenia.