Spatial Genomics Tool Maps Long-Range DNA Interactions While Preserving Cell Positions Within Tissue

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ChinaGenetics

Technology enables researchers to examine higher-level chromatin architecture while preserving the spatial context of cells in tissues by combining two approaches. These approaches represent a microfluidic spatial barcoding strategy that uses small fluid channels to assign molecular identifiers to different locations in the tissue, thereby determining where specific chromatin interactions occur, and an SPRITE-like ligation-free contact detection strategy that identifies interactions between chromatin regions without physically joining DNA fragments.

The research was published in the journal Developmental Cell.

Beyond Short-Range Chromatin Interactions

In recent years, single-cell 3D genomics technologies have made progress in understanding conformation. However, since these methods cannot preserve the spatial positions of cells within tissues, they make it difficult to examine how the genome’s architecture regulates gene expression in natural cellular environments.

Recent developments in spatial 3D genomic technologies have largely adopted ligation-based Hi-C strategies, which detect short-range chromatin interactions within a 10-megabase (Mb) window.

To address these limitations, researchers applied SpaceA to nine mouse embryo sections spanning four developmental stages from embryonic day 11.5 to 14.5 (E11.5-E14.5), generating approximately 4 TB of deep sequencing data to characterize changes in chromatin conformation during embryonic development.

Chromatin shifts during embryonic development

Researchers found that using SpaceA, A/B compartments undergo dramatic changes from E12.5 to E13.5, and that this occurs simultaneously with deep transcriptomic changes.

The team also discovered a distinct chromatin formation mechanism that operates independently of classical A/B compartment determination. Mid-range interactions (10–40 Mb) were markedly increased, interactions between neighboring compartments were strengthened, and long-range chromosomal interactions (>40 Mb) were weakened.

Microscopy revealed heterochromatin adhesion in the nuclei of liver cells, providing additional evidence for this distinct chromatin structure, which was observed alongside a global reduction in gene expression. This pattern differs from the classic model, in which gene expression is driven through A/B compartment switching or intra-compartment interactions.

Yuang Ma and colleagues, Spatially Resolved Genome Architecture in Mouse Embryonic Development, (2026). DOI: 10.1016/j.devcel.2026.09.004

Provided by the Chinese Academy of Sciences

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