Researchers have introduced a laboratory method that, for the first time in a single experiment, measures two fundamental layers of genome regulation directly inside intact tissue sections: which stretches of DNA are accessible to regulatory proteins, and how the genome is physically folded in three-dimensional space. The technique, called Spatial-ATAC-Hi-C, was described in Nature Methods and demonstrated on mammalian brain tissue, including samples from mouse brain as well as human glioblastoma and astrocytoma tumors. By capturing chromatin accessibility and chromatin architecture side by side with spatial coordinates preserved, the approach promises to reveal how the physical packaging of the genome differs from one neighborhood of cells to another within the same tissue, a dimension of biology that existing single-cell and bulk methods have largely been unable to resolve.
To appreciate why this matters, it helps to consider the two measurements the method combines. The first, chromatin accessibility, is conventionally assayed by a technique known as ATAC-seq, or assay for transposase-accessible chromatin using sequencing. ATAC-seq exploits an engineered enzyme, a hyperactive Tn5 transposase, that preferentially inserts sequencing adapters into regions of the genome that are physically open. Because open chromatin tends to correspond to active promoters, enhancers, and other regulatory elements, the density of transposase insertion at any given locus serves as a proxy for that locus’s regulatory activity. ATAC-seq has become one of the most widely used assays in genomics precisely because it is comparatively simple, requires modest amounts of material, and can be applied to single cells, yet on its own it says nothing about where in a tissue the measured cell resides or how its DNA is folded.
The second measurement, chromatin organization, is conventionally assayed by Hi-C, a method that captures the three-dimensional contacts between genomic regions. In Hi-C, DNA that is physically close together in the nucleus, even if far apart along the linear chromosome, is crosslinked, cut, ligated together, and then sequenced; the resulting contact maps reveal loops, topologically associating domains, and larger-scale compartments that shape which enhancers can reach which genes. Hi-C has been enormously influential in showing that genome folding is not a passive consequence of packaging but an active regulatory layer, with disruptions to loops and domains implicated in developmental disorders and cancer. Like ATAC-seq, however, conventional Hi-C is performed on populations of dissociated cells, which erases the spatial context in which those folding patterns occur.
Spatial-ATAC-Hi-C unites these two assays on the same thin tissue section. The general strategy follows the logic of spatial genomics platforms that have emerged over the past several years: a tissue section is placed on a substrate patterned with an array of indexed capture spots or otherwise barcoded in space, enzymatic reactions are carried out in situ, and the material released at each position is tagged with a spatial barcode before sequencing. In this case, the workflow is designed so that both the transposase-tagged fragments reporting on open chromatin and the ligation products reporting on long-range genomic contacts are captured and barcoded from the same tissue coordinates. After sequencing, computational processing separates the two modalities, producing for each spatial pixel or spot both an accessibility profile and a contact profile, alongside histological information from the underlying tissue.
The dual readout is what gives the method its distinctive power. Accessibility data alone can identify which regulatory elements are active in a given tissue region, and contact data alone can show how the genome is folded there, but the combination allows researchers to ask whether the two are coupled at the same location. A region of open chromatin sitting in a tissue microenvironment where the relevant loop is present may behave very differently from an identically open region where the loop is absent. Conversely, cell types that look similar in their accessibility profiles may differ in their higher-order folding, or vice versa. Having both measurements from the same spatial coordinates makes it possible to detect such discordances rather than inferring them by overlaying separately generated datasets, each with its own artifacts and alignment uncertainties.
The authors demonstrated the technique on mouse brain, a tissue whose elaborate cellular architecture makes it a natural testing ground for spatial genomics. The brain contains densely intermingled populations of excitatory and inhibitory neurons, astrocytes, oligodendrocytes, microglia, and other cell types arranged in layered and regionally specialized structures. Applying Spatial-ATAC-Hi-C to mouse brain sections allowed the researchers to profile chromatin accessibility and organization in a spatially resolved manner across these structures, illustrating how the method can recover spatially patterned regulatory information from a complex mammalian organ. The demonstration establishes that the chemistry and barcoding steps are compatible with intact, structurally preserved tissue rather than dissociated cells, which is the central technical hurdle for any spatial assay of this kind.
The second demonstration moved from normal tissue to disease, with applications to human glioblastoma and astrocytoma samples. Gliomas are tumors arising from glial or glial progenitor lineages, and glioblastoma in particular is among the most aggressive of human cancers, characterized by infiltrative growth, pronounced intratumoral heterogeneity, and poor responses to therapy. Spatially resolved measurements are especially valuable in this setting because the microenvironment of a tumor varies dramatically from one region to another: proliferative cores, invasive edges, hypoxic niches, and regions infiltrated by immune cells can all coexist within a single section. By co-profiling accessibility and chromatin architecture across such regions, the method offers a way to examine whether regulatory programs and genome folding differ between tumor compartments, and how tumor cells’ epigenetic states relate to their immediate surroundings.
For cancer biology, the ability to measure chromatin architecture in situ is particularly intriguing. Genome folding alterations, including changes in topologically associating domains and enhancer-promoter loops, have been implicated in oncogene activation and tumor suppressor silencing, but these observations have mostly come from cell lines or dissociated tumors, where the relationship between folding and tissue context is lost. A spatial assay that preserves histological landmarks means that contact maps can be interpreted alongside the pathology visible in the section, connecting molecular events to morphological features such as tumor margins or regions of distinct grade. The same logic applies to accessibility: enhancer activity in an invasive edge cell can be compared directly with that in a cell at the tumor core, without the confounding of bulk averaging.
Like all emerging technologies, Spatial-ATAC-Hi-C comes with considerations that will shape its adoption. Spatial assays of chromatin generally trade off resolution, throughput, and sensitivity: capturing both short fragments from transposase tagmentation and long-range ligation products from the same section is chemically demanding, and the amount of informative data recoverable per spatial unit depends on the size of the spots, the thickness of the section, and the depth of sequencing. Computational analysis is also more involved than for either assay alone, since contact maps are sparse at single-spot resolution and typically require aggregation, imputation, or specialized visualization to interpret. The authors’ demonstrations on mouse brain and human glioma samples suggest these challenges are tractable, but as with any new platform, broader adoption will depend on reproducibility across laboratories, tissue types, and sample qualities, including archived or clinically derived specimens.
Even so, the arrival of a method that co-profiles chromatin accessibility and spatial genome organization marks a meaningful expansion of the spatial genomics toolkit. Until now, researchers studying gene regulation in tissues have had to choose between knowing where a regulatory state occurs and knowing how the genome is physically configured, or else stitch together separate experiments. Spatial-ATAC-Hi-C closes that gap, opening the possibility of systematically mapping how the folded genome varies across development, physiology, and disease within the native architecture of organs. For fields ranging from neurobiology to cancer research, where epigenetic state and tissue context are inseparable determinants of cell behavior, the ability to read both layers of regulation from the same tissue section is likely to find rapid and wide application.
Subject of Research: Spatially resolved co-profiling of chromatin accessibility and three-dimensional chromatin architecture in mammalian tissues
Article Title: Spatial chromatin architecture and accessibility co-profiling of mammalian tissues
Article References: Wang, P., Wang, J., Wang, Q., Youngblood, M. W., Cheng, Y., Tao, B., Wong, J. H.-Y., Luan, Y., Yu, S., Swaroop, A., Nandoliya, K. R., Najem, H., Fu, Y., McCortney, K., Zhang, D., Diao, Y., Heimberger, A. B., Sonabend, A. M., Horbinski, C. M., … Yue, F. (2026). Spatial chromatin architecture and accessibility co-profiling of mammalian tissues. Nature Methods. https://doi.org/10.1038/s41592-026-03217-4
Image Credits: AI Generated
DOI: 10.1038/s41592-026-03217-4
Keywords: Spatial-ATAC-Hi-C, chromatin accessibility, chromatin architecture, spatial genomics, ATAC-seq, Hi-C, mouse brain, glioblastoma, astrocytoma, epigenomics, gene regulation, Nature Methods
Cite Scienmag News
APA MLA Chicago
Juliet Wilcox. (September 22, 2026). New Method Maps Both Chromatin Access and 3D Folding in Intact Tissues. Scienmag. https://scienmag.com/new-method-maps-both-chromatin-access-and-3d-folding-in-intact-tissues/
Juliet Wilcox. “New Method Maps Both Chromatin Access and 3D Folding in Intact Tissues.” Scienmag, 22 September 2026, https://scienmag.com/new-method-maps-both-chromatin-access-and-3d-folding-in-intact-tissues/. Accessed 22 September 2026.
Juliet Wilcox. “New Method Maps Both Chromatin Access and 3D Folding in Intact Tissues.” Scienmag. September 22, 2026. https://scienmag.com/new-method-maps-both-chromatin-access-and-3d-folding-in-intact-tissues/
Copy citation Download RIS
Tags: 3D chromatin structure in tumors3D genome foldingastrocytomaATAC-seqChromatin Accessibilitychromatin accessibility in brain tissuechromatin accessibility mappingchromatin architectureepigenomicsGene regulationgenome architecture in tissueGlioblastomaHi-Cintact tissue chromatin analysisintegrated chromatin accessibility and architecturemouse brainmulti-dimensional genome regulationNature Methodssingle-tissue genome mappingspatial genome regulationspatial genomicsspatial genomics methodsSpatial-ATAC-Hi-CSpatial-ATAC-Hi-C technique
