Researchers led by professor Li Xiang at the Chinese Academy of Sciences have developed SpaceA, a spatial 3D genomics technology that maps long-range DNA interactions while preserving cells’ locations within tissue sections. The method combines microfluidic spatial barcoding with a ligation-free contact detection strategy to profile higher-order chromatin architecture.
DNA inside the nucleus is packaged with proteins into chromatin and folded into intricate three-dimensional structures. Although scientists have studied these conformations for years, standard single-cell 3D genomics techniques cannot preserve the spatial positions of cells within native tissues, making it difficult to connect genome architecture directly to gene expression. More recently, spatial genomics tools adopted ligation-based Hi-C methods, which primarily capture short-range chromatin interactions within 10 megabases.
SpaceA was engineered by a team of scientists directed by professor Li Xiang, representing the Chinese Academy of Sciences (CAS) and its Institute of Genetics and Developmental Biology (IGDB), in order to address these obstacles. Their findings appear in the journal Developmental Cell, detailing a system built for high-confidence, in situ profiling of long-range chromatin interactions inside tissue sections.
Combining Microfluidic Barcoding and Contact Detection
SpaceA pairs two core methodologies to investigate higher-order chromatin architecture while keeping cellular spatial context intact. First, microfluidic spatial barcoding uses microscopic fluid channels to assign distinct molecular identifiers to different tissue locations, allowing investigators to track precisely where specific chromatin interactions take place.
Second, the technology incorporates a SPRITE-like ligation-free contact detection strategy. This approach detects physical interactions between chromatin regions without requiring researchers to physically join DNA fragments together.
Mapping Mouse Embryo Development Across Four Stages
The investigators put the system through its paces by deploying SpaceA across nine distinct sections of mouse embryos that covered four separate phases of development, running from E11.5 to E14.5 (embryonic days 11.5 to 14.5). This deep sequencing effort generated approximately 4 TB of data to chart shifts in chromatin conformation during embryonic development.
Using the platform, the researchers tracked how A/B compartments undergo a dramatic transition between E12.5 and E13.5, a window that coincides with profound transcriptomic changes.
Discovering Chromatin Assembly in the Embryonic Liver
The study also uncovered a distinct chromatin assembly mechanism operating inside the embryonic liver that functions independently of classical A/B compartment determination. In this tissue, mid-range interactions (10–40 Mb) were significantly enhanced. Furthermore, interactions between adjacent compartments grew stronger, while long-range interchromosomal interactions (>40 Mb) weakened.
Microscopy confirmed heterochromatin adhesion within liver cell nuclei, supporting this distinct structural model, which coincided with a global decline in gene expression. This deviates from the classical model where gene expression is promoted through A/B compartment switching or intracompartmental interactions.