Genomic and Transcriptomic Signatures of SETD1A Disruption in Human Excitatory Neuron Development and Psychiatric Disease Risk.

ABSTRACT: Genetic disruption of SETD1A markedly increases the risk for schizophrenia. To elucidate the underlying mechanisms, we generated isogenic organoid models of the developing human cerebral cortex harboring a SETD1A loss-of-function schizophrenia risk mutation. Employing chromatin profiling combined with RNA sequencing, we identified high-confidence SETD1A target genes, analyzed the impact of the mutation on SETD1A binding and transcriptional regulation and validated key findings with orthogonal approaches. Disruption of SETD1A function disturbs the finely tuned temporal gene expression in the excitatory neuron lineage, yielding an aberrant transcriptional program that compromises key regulatory and metabolic pathways essential for neurodevelopmental transitions. Although overall SETD1

SUBMITTER: Sun Z 

PROVIDER: S-EPMC11974865 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature