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; Chongyuan Luo

doi:10.1038/s41586-024-08030-7

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

Nature. 2024 Nov;635(8038):481-489. doi: 10.1038/s41586-024-08030-7. Epub 2024 Oct 9.

Authors

Matthew G Heffel^#^{1

2}, Jingtian Zhou^#^{3

4

5}, Yi Zhang^#¹, Dong-Sung Lee^#^{6

7}, Kangcheng Hou^#^{2

8

9}, Oier Pastor-Alonso¹⁰, Kevin D Abuhanna¹, Joseph Galasso^{1

2

11}, Colin Kern¹², Chu-Yi Tai¹², Carlos Garcia-Padilla^{12

13}, Mahsa Nafisi¹³, Yi Zhou¹³, Anthony D Schmitt¹⁴, Terence Li^{1

2}, Maximilian Haeussler¹⁵, Brittney Wick¹⁵, Martin Jinye Zhang^{16

17}, Fangming Xie^{11

18}, Ryan S Ziffra^{19

20

21

22}, Eran A Mukamel¹⁸, Eleazar Eskin²³, Tomasz J Nowakowski^{19

20

21

22}, Jesse R Dixon²⁴, Bogdan Pasaniuc^{8

9}, Joseph R Ecker^{3

25}, Quan Zhu¹², Bogdan Bintu¹³, Mercedes F Paredes^{26

27

28

29}, Chongyuan Luo³⁰

Affiliations

¹ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
² Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
³ Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
⁴ Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
⁵ Arc Institute, Palo Alto, CA, USA.
⁶ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
⁷ Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹² Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
¹³ Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
¹⁴ Arima Genomics, Carlsbad, CA, USA.
¹⁵ Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
¹⁶ Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
¹⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁸ Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
¹⁹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
²¹ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
²² Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
²³ Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
²⁴ Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
²⁵ Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, USA.
²⁶ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Mercedes.Paredes@ucsf.edu.
²⁷ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Mercedes.Paredes@ucsf.edu.
²⁸ Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA. Mercedes.Paredes@ucsf.edu.
²⁹ Developmental Stem Cell Biology, University of California, San Francisco, San Francisco, CA, USA. Mercedes.Paredes@ucsf.edu.
³⁰ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. cluo@mednet.ucla.edu.

^# Contributed equally.

Abstract

The human hippocampus and prefrontal cortex play critical roles in learning and cognition^1,2, 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.

MeSH terms

Cell Differentiation / genetics
Chromatin* / chemistry
Chromatin* / genetics
Chromatin* / metabolism
DNA Methylation* / genetics
Disease Susceptibility
Epigenesis, Genetic*
Epigenomics
Fetus / cytology
Fetus / embryology
Fetus / metabolism
Hippocampus* / cytology
Hippocampus* / embryology
Hippocampus* / growth & development
Hippocampus* / metabolism
Humans
Infant, Newborn
Multiomics*
Neuroglia / cytology
Neuroglia / metabolism
Neurons / cytology
Neurons / metabolism
Prefrontal Cortex* / cytology
Prefrontal Cortex* / embryology
Prefrontal Cortex* / growth & development
Prefrontal Cortex* / metabolism
Schizophrenia / genetics
Schizophrenia / metabolism
Single Molecule Imaging
Single-Cell Analysis
Time Factors

Substances

Chromatin

Abstract

MeSH terms

Substances

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