한빛사논문
Matthew G. Heffel 1,2,29, Jingtian Zhou 3,4,5,29, Yi Zhang 1,29, Dong-Sung Lee 6,7,29, Kangcheng Hou 2,8,9,29, Oier Pastor-Alonso 10, Kevin D. Abuhanna 1, Joseph Galasso 1,2,11, Colin Kern 12, Chu-Yi Tai 12, Carlos Garcia-Padilla 12,13, Mahsa Nafisi 13, Yi Zhou 13, Anthony D. Schmitt 14, Terence Li 1,2, Maximilian Haeussler 15, Brittney Wick 15, Martin Jinye Zhang 16,17, Fangming Xie 11,18, Ryan S. Ziffra 19,20,21,22, Eran A. Mukamel 18, Eleazar Eskin 23, Tomasz J. Nowakowski 19,20,21,22, Jesse R. Dixon 24, Bogdan Pasaniuc 8,9, Joseph R. Ecker 3,25, Quan Zhu 12, Bogdan Bintu 13, Mercedes F. Paredes 8,26,27,28,* & Chongyuan Luo 1,*
1Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
2Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
3Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
4Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
5Arc Institute, Palo Alto, CA, USA.
6Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
7Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
8Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
9Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
10Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
11Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
12Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
13Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
14Arima Genomics, Carlsbad, CA, USA.
15Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
16Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
17Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
18Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
19Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
20Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
21Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
22Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
23Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
24Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
25Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, USA.
26Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
27Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
28Developmental Stem Cell Biology, University of California, San Francisco, San Francisco, CA, USA.
29These authors contributed equally: Matthew G. Heffel, Jingtian Zhou, Yi Zhang, Dong-Sung Lee, Kangcheng Hou.
*Corresponding authors: correspondence to Mercedes F. Paredes or Chongyuan Luo
Abstract
The human hippocampus and prefrontal cortex play critical roles in learning and cognition, 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). 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.
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