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However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly processed newly generated Hi-C data from iPSC-derived neurons and neurons isolated from the human postmortem brain, together with previously published data sets comprising 228 human and 89 mouse Hi-C and snm3C-seq samples from different cell subtypes. These data were merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain the 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. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and postmortem neuronal data sets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. 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.<\/jats:p>","DOI":"10.1101\/gr.281488.125","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:55:17Z","timestamp":1785776117000},"page":"1977-1996","source":"Crossref","is-referenced-by-count":0,"title":["Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling"],"prefix":"10.1101","volume":"36","author":[{"given":"Diana R.","family":"Zagirova","sequence":"first","affiliation":[{"name":"Center for Molecular and Cellular Biology, Territory of Innovation Center Skolkovo, Moscow 121205, Russia;"},{"name":"A.A. 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