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

LU, L.; Liu, X.; Huang, W.-K.; Giusti-Rodriguez, P.; Cui, J.; Zhang, S.; Xu, W.; Wen, Z.; Ma, S.; Rosen, J. D.; Xu, Z.; Bartels, C.; Riki Kawaguchi, R.; Hu, M.; Scacheri, P.; Rong, Z.; Li, Y.; Sullivan, P. F.; Song, H.; Ming, G.-l.; Jin, F.

doi:10.1101/744540

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bioRxiv · 10.1101/744540

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

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Abstract

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

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LU, L., Liu, X., Huang, W.-K., Giusti-Rodriguez, P., Cui, J., Zhang, S., Xu, W., Wen, Z., Ma, S., Rosen, J. D., Xu, Z., Bartels, C., Riki Kawaguchi, R., Hu, M., Scacheri, P., Rong, Z., Li, Y., Sullivan, P. F., Song, H., Ming, G.-l., Jin, F.. 2019-08-22. Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution. https://doi.org/10.1101/744540

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