TRANSCRIPTIONAL CONSEQUENCES OF REDUCED EXPRESSION OF THE SCHIZOPHRENIA SUSCEPTIBILITY GENE SETD1A

Background Loss of function alleles in SETD1A are a genetic risk factor for developing schizophrenia. SETD1A encodes a protein possessing histone methyltransferase activity. Specifically, it catalyses the methylation of histone H3 at Lys4, a modification indicative of active regulatory DNA function. Reduced SETD1A expression is therefore likely to have a major impact on global gene expression via alterations to the histone code. To understand the downstream genes and pathways altered by SETD1A expression we performed gene expression profiling of a neural cell line in which SETD1A expression had been reduced. Methods SETD1A expression was reduced in the SH-SY5Y neuroblastoma cell line using two non-overlapping siRNAs. A non-targeting siRNA was used as a control. Four days after transfection cells were harvested for RNA extraction. Transcriptional profiling was performed using Illumina microarrays. Differential expressed probes were identified using t tests and gene ontology enrichment analysis performed using DAVID. Quantitative PCR was used to verify the microarray findings for a subset of gene transcripts. We tested for enrichment of association with schizophrenia amongst the differential expressed probes using MAGMA. Results Both targeting siRNAs reduced SETD1A RNA expression ~50% compared to control. Gene expression profiling identified 1131 differentially expressed probes (p Discussion Reduced SETD1A levels lead to widespread changes in the expression of genes involved in diverse process, consistent with its role in general transcription. However, we observed altered expression of known regulators of neuronal development and function. Our results also highlight mitochondrial function as important downstream consequences of reduced SETD1A expression. Importantly, we show that gene expression changes after knock-down of a rare variant schizophrenia risk gene are enriched for a common variant association signal, indicating a point of molecular convergence in risk mechanisms.