Establishment of a Common Marmoset Lineage Carrying a Frameshift Mutation in SETD1A, a Schizophrenia Risk Gene.

Abstract

Appropriate histone modifications are essential for maintaining functional chromatin structure and gene expression, and dysfunction of their regulators has been linked to a variety of diseases. Among these modifications, trimethylation of lysine 4 on histone H3 (H3K4me3) is a well-characterized epigenetic mark enriched at transcription start sites of actively transcribed genes. H3K4me3 regulates gene transcription by recruiting transcription factors, facilitating chromatin accessibility, and preventing DNA methylation. In mammals, methylation of H3K4 is catalyzed by a family of histone methyltransferases including SET domain containing 1A (SETD1A), which is primarily responsible for genome-wide deposition of H3K4me2/3. Loss-of-function variants in SETD1A, highlighting its critical role in brain development and cognitive function, are strongly associated with schizophrenia (SCZ) and other neurodevelopmental disorders, but the underlying mechanisms remain largely unclear. To better understand the epigenetic and neurobiological consequences of SETD1A dysfunction, non-human primate models can serve as a useful tool because of their close evolutionary relationship to humans and highly developed cognitive abilities. In this study, we established a genetically engineered common marmoset (Callithrix jacchus) lineage carrying a frameshift mutation in SETD1A, which is, to the best of our knowledge, the first non-human primate lineage carrying a mutation in an epigenetic regulatory gene associated with SCZ, and confirmed germline transmission of the mutant allele. In a comparison between fibroblasts derived from one SETD1A mutant and one wild-type marmoset, the mutant showed a lower SETD1A protein level, modest differences in H3K4me3 deposition, and broader differences in gene expression profiles. Although these molecular observations require validation using additional biological replicates, the establishment of this SETD1A mutant marmoset lineage provides a valuable platform for bridging molecular mechanisms with primate neurobiology and for investigating the role of epigenetic regulation in the pathophysiology of neuropsychiatric and neurodevelopmental disorders.