Fetal signatures in the 3D genome of iPSC-derived neurons: implications for disease modeling

Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we collected and uniformly processed more than 300 human and mouse neuronal Hi-C datasets and examined chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We found that iPSC-derived neurons largely retain chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Conversely, these cells robustly capture contacts involving GWAS SNPs relevant to neurological diseases. Thus, while iPSC-derived neurons may not fully replicate 3D genome architecture of adult neurons, they effectively model interactions linking disease-associated SNPs to target genes. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.