Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input \"easy Hi-C\" (eHi-C) protocol to map the 3D genome architecture in neurogenesis and brain tissues, and also developed an improved Hi-C bias-correction pipeline (HiCorr) enabling better identification of enhancer loops or aggregates at sub-TAD level. We compared ultra-deep 3D genome maps from 10 human tissue- or cell types, with a focus on stem cells and neural development. We found several large loci in skin-derived human iPSC lines showing recurrent 3D compartmental memory of somatic heterochromatin. Chromatin loop interactions, but not genome compartments, are hallmarks of neural differentiation. Interestingly, we observed many cell type- or differentiation-specific enhancer aggregates spanning large neighborhoods, supporting a phase-separation mechanism that stabilizes enhancer contacts during development. Finally, we demonstrated that chromatin loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.\n\nHighlightsO_LILow input \"easy Hi-C\" protocol compatible with 50-100K cells\nC_LIO_LIImproved Hi-C bias correction allows direct observation and accurate identification of sub-TAD chromatin loops and enhancer aggregates\nC_LIO_LIRecurrent architectural memory of somatic heterochromatin at compartment level in skin-derived hiPSCs\nC_LIO_LIChromatin loop, but not genome compartment, marks neural differentiation\nC_LIO_LIChromatin loop outperforms eQTL in defining brain GWAS target genes\nC_LI