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Single-cell nuclear architecture across cell types in the mouse brain

Takei, Yodai and Zheng, Shiwei and Yun, Jina and Shah, Sheel and Pierson, Nico and White, Jonathan and Schindler, Simone and Tischbirek, Carsten H. and Yuan, Guo-Cheng and Cai, Long (2021) Single-cell nuclear architecture across cell types in the mouse brain. Science, 374 (6567). pp. 586-594. ISSN 0036-8075. doi:10.1126/science.abj1966.

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Diverse cell types in tissues have distinct gene expression programs, chromatin states, and nuclear architectures. To correlate such multimodal information across thousands of single cells in mouse brain tissue sections, we use integrated spatial genomics, imaging thousands of genomic loci along with RNAs and epigenetic markers simultaneously in individual cells. We reveal that cell type–specific association and scaffolding of DNA loci around nuclear bodies organize the nuclear architecture and correlate with differential expression levels in different cell types. At the submegabase level, active and inactive X chromosomes access similar domain structures in single cells despite distinct epigenetic and expression states. This work represents a major step forward in linking single-cell three-dimensional nuclear architecture, gene expression, and epigenetic modifications in a native tissue context.

Item Type:Article
Related URLs:
URLURL TypeDescription ItemCode
Takei, Yodai0000-0002-7226-5185
Zheng, Shiwei0000-0001-6682-6743
Yun, Jina0000-0002-7792-3749
Pierson, Nico0000-0002-2451-0633
White, Jonathan0000-0002-7009-3332
Schindler, Simone0000-0003-1028-3115
Tischbirek, Carsten H.0000-0002-6876-3448
Yuan, Guo-Cheng0000-0002-2283-4714
Cai, Long0000-0002-7154-5361
Additional Information:© 2021 American Association for the Advancement of Science. Received 26 April 2021; accepted 15 September 2021. Published online 30 September 2021. We thank N. Ollikainen and M. Guttman for help with Hi-C analysis; R. J. Oakey for providing the processed ChIP-seq data; C.-H. L. Eng for helpful discussion; C. Karp for making custom-made flow cells; L. Sanchez and E. Buitrago-Delgado for help with the perfusion setup; I. Strazhnik for help with figures; and A. Anderson for help with the manuscript. This work was supported by NIH 4DN DA047732 and supplement (L.C.) and by the Paul G. Allen Frontiers Foundation Discovery Center (L.C.). Author contributions: Y.T. and L.C. conceived of the idea and designed experiments. Y.T. designed probes with input from C.H.T. Y.T., J.Y., and S.Sc. prepared and validated experimental materials. Y.T. performed imaging experiments. Y.T., S.Sh., N.P., and J.W. wrote image processing scripts, and Y.T. performed image processing. Y.T., S.Z., and L.C. analyzed data with input from G.-C.Y. Y.T. and L.C. wrote the manuscript with input from S.Z., C.H.T., and G.-C.Y. L.C. supervised all aspects of the projects. Competing interests: L.C. is a cofounder of Spatial Genomics, Inc. Data and materials availability: The custom-written scripts and seqFISH probe sequences used in this study are available in a Zenodo repository (18) associated with a GitHub repository ( The source data and processed data from this study are available in a Zenodo repository (23).
Funding AgencyGrant Number
NIH4DN DA047732
Paul G. Allen Frontiers GroupUNSPECIFIED
Issue or Number:6567
Record Number:CaltechAUTHORS:20211004-203742730
Persistent URL:
Official Citation:Single-cell nuclear architecture across cell types in the mouse brain. Y. Takei et al., Science, 374 (6567); DOI: 10.1126/science.abj1966
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111179
Deposited By: Tony Diaz
Deposited On:04 Oct 2021 20:46
Last Modified:02 Nov 2021 21:20

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