New Spatial 3D Genomics Technique Enables In Situ Profiling of Long-Range Chromatin Interactions

A team led by LI Xiang at the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences has developed SpaceA, a spatial 3D genomics technology that allows high-confidence, in situ profiling of long-range chromatin interactions within tissue sections, addressing a gap left by existing single-cell and spatial genomics methods. The technique is described in a paper recently published in Developmental Cell.

Single-cell 3D genomics methods have advanced the understanding of chromatin conformation, but they can’t preserve the spatial position of cells within tissue, making it hard to study how genome architecture regulates gene expression in its native cellular environment. More recent spatial 3D genomics technologies have relied on ligation-based Hi-C strategies, which tend to favor detection of short-range chromatin interactions within 10 megabases, leaving longer-range interactions underexplored.

SpaceA addresses both limitations by combining two approaches: microfluidic spatial barcoding, which uses tiny fluid channels to assign molecular identifiers to specific locations within a tissue so researchers can pinpoint where chromatin interactions occur, and a SPRITE-like, ligation-free contact detection strategy, which identifies interactions between chromatin regions without physically joining DNA fragments together. Combined, these approaches let researchers study higher-order chromatin architecture while keeping the spatial context of cells in tissue intact.

To test the technology, the researchers applied SpaceA to nine mouse embryo sections spanning four developmental stages, from embryonic day 11.5 to 14.5 (E11.5 to E14.5), generating roughly 4 TB of deeply sequenced data to track how chromatin conformation changes during embryonic development. The analysis showed that A/B compartments, a basic unit of chromatin organization, underwent a dramatic transition between E12.5 and E13.5, coinciding with major transcriptomic changes at that same developmental window. 

In the embryonic liver, the team identified a distinct chromatin assembly mechanism that operates independently of classical A/B compartment determination. Mid-range interactions (10–40 Mb) were significantly enhanced, interactions between adjacent compartments were strengthened, and long-range interchromosomal interactions (greater than 40 Mb) were weakened. Microscopy confirmed this distinct structure, revealing heterochromatin adhesion in liver cell nuclei, which was accompanied by a global decline in gene expression. That pattern runs counter to the classical model, in which gene expression is typically promoted through A/B compartment switching or interactions within a compartment, suggesting the liver follows a different chromatin organization strategy during this developmental window.