Schizophrenia risk gene ZNF536 modulates retinoic acid response and neuronal gene networks in SH-SY5Y cells

ZNF536, a brain-specific transcriptional repressor, has recently emerged as a candidate risk gene for schizophrenia (SZ), yet its functional role in human neurodevelopment remains poorly understood. In this study, we used CRISPR/Cas9 genome editing to generate a dual-allelic ZNF536 knockout model in SH-SY5Y cells, combining a 103 kb deletion encompassing SZ-associated intronic regions with a disruption of zinc finger domains in exon 2. Transcriptome profiling of mutant cells undergoing all-trans retinoic acid (ATRA)-induced differentiation revealed impaired activation of retinoic acid receptor (RAR) target genes, reduced neurite outgrowth, and failure of neuronal maturation. Notably, gene set enrichment analysis uncovered dysregulation of E2F4-mediated cell cycle pathways, suggesting that ZNF536 modulates neurogenic commitment through coordinated control of transcriptional repression and cell proliferation. Moreover, the targeted intronic deletion altered the expression of multiple SZ-associated genes, supporting the functional importance of cis-regulatory elements within ZNF536. Together, our results identify ZNF536 as a critical regulator of RA-responsive gene networks and neuronal differentiation, offering new mechanistic insights into its contribution to schizophrenia (SZ) pathogenesis.