3D-genome impacts of TAD-boundary-disrupting ultra-rare structural variants identified in schizophrenia

Two TAD-boundary-disrupting ultra-rare structural variants reshaped 3D-genome organization and transcriptional networks in a cell-type-specific manner in CRISPR-engineered iPSC-derived neurons.

• Why it matters: Schizophrenia is linked to ultrarare SVs that localize to TAD boundaries, but how these variants alter enhancer–promoter contacts and gene regulation remains unclear.
• What they did: The authors engineered two TAD-boundary-disrupting SVs in isogenic iPSCs with CRISPR/Cas9, differentiated them into neuronal precursor cells, excitatory glutamatergic neurons, and medium spiny neurons, then used chromatin conformation capture (Hi-C) and RNA sequencing.
• The result: The variants could reshape 3D-genome and transcriptional networks differently across neuronal cell types, supporting a mechanistic link between TAD-boundary disruption and gene-expression changes.