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

Author

Listed:
  • Matthew G. Heffel

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Jingtian Zhou

    (The Salk Institute for Biological Studies
    University of California, San Diego
    Arc Institute)

  • Yi Zhang

    (University of California, Los Angeles)

  • Dong-Sung Lee

    (Seoul National University Graduate School
    Seoul National University)

  • Kangcheng Hou

    (University of California, Los Angeles
    University of California, Los Angeles
    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
    University of California, Los Angeles
    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
    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
    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
    Harvard T.H. Chan School of Public Health)

  • Fangming Xie

    (University of California, Los Angeles
    University of California, San Diego)

  • Ryan S. Ziffra

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco
    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
    University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Jesse R. Dixon

    (The Salk Institute for Biological Studies)

  • Bogdan Pasaniuc

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Joseph R. Ecker

    (The Salk Institute for Biological Studies
    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
    University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Chongyuan Luo

    (University of California, Los Angeles)

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.

Suggested Citation

  • 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 , 2024. "Temporally distinct 3D multi-omic dynamics in the developing human brain," Nature, Nature, vol. 635(8038), pages 481-489, November.
    • Handle: RePEc:nat:nature:v:635:y:2024:i:8038:d:10.1038_s41586-024-08030-7
    DOI: 10.1038/s41586-024-08030-7
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