Temporally distinct 3D multi-omic dynamics in the developing human brain

Matthew G. Heffel, Jingtian Zhou, Yi Zhang, Dong-Sung Lee, Kangcheng Hou, Oier Pastor-Alonso, Kevin D. Abuhanna, Joseph Galasso, Colin Kern, Chu-Yi Tai, Carlos Garcia-Padilla, Mahsa Nafisi, Yi Zhou, Anthony D. Schmitt, Terence Li, Maximilian Haeussler, Brittney Wick, Martin Jinye Zhang, Fangming Xie, Ryan S. Ziffra, Eran A. Mukamel, Eleazar Eskin, Tomasz J. Nowakowski, Jesse R. Dixon, Bogdan Pasaniuc, Joseph R. Ecker, Quan Zhu, Bogdan Bintu, Mercedes F. Paredes () and Chongyuan Luo ()
Additional contact information
Matthew G. Heffel: University of California, Los Angeles
Jingtian Zhou: The Salk Institute for Biological Studies
Yi Zhang: University of California, Los Angeles
Dong-Sung Lee: Seoul National University Graduate School
Kangcheng Hou: University of California, Los Angeles
Oier Pastor-Alonso: University of California, San Francisco
Kevin D. Abuhanna: University of California, Los Angeles
Joseph Galasso: University of California, Los Angeles
Colin Kern: University of California, San Diego
Chu-Yi Tai: University of California, San Diego
Carlos Garcia-Padilla: University of California, San Diego
Mahsa Nafisi: University of California, San Diego
Yi Zhou: University of California, San Diego
Anthony D. Schmitt: Arima Genomics
Terence Li: University of California, Los Angeles
Maximilian Haeussler: University of California, Santa Cruz
Brittney Wick: University of California, Santa Cruz
Martin Jinye Zhang: Carnegie Mellon University
Fangming Xie: University of California, Los Angeles
Ryan S. Ziffra: University of California, San Francisco
Eran A. Mukamel: University of California, San Diego
Eleazar Eskin: University of California, Los Angeles
Tomasz J. Nowakowski: University of California, San Francisco
Jesse R. Dixon: The Salk Institute for Biological Studies
Bogdan Pasaniuc: University of California, Los Angeles
Joseph R. Ecker: The Salk Institute for Biological Studies
Quan Zhu: University of California, San Diego
Bogdan Bintu: University of California, San Diego
Mercedes F. Paredes: University of California, Los Angeles
Chongyuan Luo: University of California, Los Angeles

Nature, 2024, vol. 635, issue 8038, 481-489

Abstract: Abstract The human hippocampus and prefrontal cortex play critical roles in learning and cognition1,2, yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-dimensional chromatin conformational reorganization during the development of the hippocampus and prefrontal cortex, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation generated by single-nucleus methyl-3C sequencing (snm3C-seq3)3. The remodelling of DNA methylation is temporally separated from chromatin conformation dynamics. Using single-cell profiling and multimodal single-molecule imaging approaches, we have found that short-range chromatin interactions are enriched in neurons, whereas long-range interactions are enriched in glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type development and differentiation, finding putatively causal common variants for schizophrenia strongly overlapping with chromatin loop-connected, cell-type-specific regulatory regions. Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci.

Date: 2024
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DOI: 10.1038/s41586-024-08030-7

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