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. 2023 Sep 8;381(6662):1112-1119.
doi: 10.1126/science.adh3253. Epub 2023 Sep 7.

Lifelong restructuring of 3D genome architecture in cerebellar granule cells

Longzhi Tan #  1   2 , Jenny Shi #  1   2   3 , Siavash Moghadami  1   4 , Bibudha Parasar  1 , Cydney P Wright  1   5 , Yunji Seo  1 , Kristen Vallejo  6 , Inma Cobos  6 , Laramie Duncan  7 , Ritchie Chen  2 , Karl Deisseroth  2   7   8
Affiliations

Lifelong restructuring of 3D genome architecture in cerebellar granule cells

Longzhi Tan et al. Science. .

Abstract

The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.

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Conflict of interest statement

Competing interests: LT is an inventor on the Dip-C patent US 11,530,436 (“Multiplex end-tagging amplification of nucleic acids”). KD is a co-founder and Scientific Advisory Board member of Stellaromics and Maplight Therapeutics, and Scientific Advisory Board member of BrightMinds Biosciences.

Figures

Fig. 1.
Fig. 1.. 3D genome atlas across lifespan for human and mouse cerebellum with multi-ome atlas of postnatal development.
(A) Study design. (B) Integrative transcriptome analysis of human multi-ome samples. (C) Representative expression profiles of marker genes.
Fig. 2.
Fig. 2.. Simultaneous transcriptome and chromatin accessibility profiling revealed continuous maturation of cerebellar granule cells over the first postnatal year.
(A) Stages of granule cell maturation, their marker genes (ranked by specificity), and enriched pathways (summarized for the top 100 genes). (B) Maturation pseudotime analysis of each sample.
Fig. 3.
Fig. 3.. High-throughput, high-precision 3D genome profiling uncovered lifelong genome remodeling in the human and mouse cerebellum.
(A) Pop-C method. (B) vDip-C method. (C–D) Cross-species 3D genome atlas for the developing and aging cerebellum (with cerebral cortex as counterpoint). Pearson’s r (and p-value) was calculated from logarithm of age.
Fig. 4.
Fig. 4.. Cerebellar granule cells formed ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts during development and aging.
(A) Distribution of genomic distances of chromatin contacts. (B) Aggregated contact maps for an example chromosome and a zoomed-in region (upper right triangles). Zoomed-in regions are homologous. Dashed boxes highlight prominent changes. Bin size: 250 kb. (C) Aggregated inter-chromosomal contact maps. Bin sizes: 6 Mb (human); 5 Mb (mouse); 500 kb (zoom-in).
Fig. 5.
Fig. 5.. Lifelong maturation of chromatin A/B compartments was associated with cerebellar granule cell–specific genes.
(A) Mean scA/B of each dynamic 1-Mb region at each stage (left). Rows are ordered by hierarchical clustering; the two clusters were visualized on t-SNE plots (right). As in (5), scA/B calculation excludes contacts within each region and thus primarily reports on long-range interactions. (B) Mean scA/B of each 1-Mb region harboring granule cell–specific marker genes (14) at each stage (left), with aggregated scA/B shown on t-SNE plots (right). (C). Aggregated contact maps for an example gene. Bin size: 100 kb. (D) Schematic of transcriptional etching.
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References

    1. Chi Y, Shi J, Xing D, Tan L, Every gene everywhere all at once: High-precision measurement of 3D chromosome architecture with single-cell Hi-C. Frontiers in Molecular Biosciences. 9 (2022). - PMC - PubMed
    1. Tan L, Xing D, Chang C-H, Li H, Xie XS, Three-dimensional genome structures of single diploid human cells. Science. 361, 924–928 (2018). - PMC - PubMed
    1. Tan L, Xing D, Daley N, Xie XS, Three-dimensional genome structures of single sensory neurons in mouse visual and olfactory systems. Nat Struct Mol Biol. 26, 297–307 (2019). - PubMed
    1. Tan L, Determining the 3D genome structure of a single mammalian cell with Dip-C. STAR Protocols. 2, 100622 (2021). - PMC - PubMed
    1. Tan L, Ma W, Wu H, Zheng Y, Xing D, Chen R, Li X, Daley N, Deisseroth K, Xie XS, Changes in genome architecture and transcriptional dynamics progress independently of sensory experience during post-natal brain development. Cell. 184, 741–758.e17 (2021). - PubMed

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