SETD1A Regulates Psychiatric Gene Networks Involved in Genomic Stability and Synaptic Function in Rare and Sporadic Schizophrenia
Rare loss-of-function (LoF) mutations in SETD1A are associated with schizophrenia (SCZ). However, how SETD1A haploinsufficiency leads to SCZ-associated phenotypes and its relevance to patients without these rare mutations is unknown. Here, we identify SETD1A bound loci and regulated genes in human prenatal cortex and isogenic pluripotent stem cell-derived neuronal models engineered with SETD1A LoF variants, including the most common patient mutation. SETD1A preferentially binds the promoters of SCZ and Bipolar risk loci that regulate chromatin remodeling, DNA repair, and synaptic function. Additionally, SETD1A binds to DNA damage prone sites in neural progenitor cells and postmitotic neurons. SETD1A haploinsufficiency causes accelerated neurogenesis, reduced neuronal complexity, and DNA damage accumulation in postmitotic neurons that is rescued by inhibiting the H3K4me2/3 demethylase KDM5. In postmortem SCZ cortical tissue, individuals who lack SETD1A mutations exhibit reduced SETD1A expression, associated with downregulation of SETD1A-regulated genes, implicating SETD1A-H3K4me dysfunction in sporadic SCZ cases. Therefore, restoring the SETD1A-H3K4me epigenetic imbalance may benefit individuals with SETD1A haploinsufficiency as well as a broader psychiatric population without SETD1A mutations. Overall design: Single Cell RNA-seq profiling of human Cerebral Organoids engineered with SETD1A LoF variants.