Spatial-ATAC-Hi-C maps 2,500 positions across brain and tumor tissue

Fifty horizontal and 50 vertical microchannels create a grid of up to 2,500 positions on one tissue section. Each position covers a 50 × 50 micrometer square and typically contains 3 to 21 cells. Spatial-ATAC-Hi-C, a method published in Nature Methods on September 1, simultaneously maps three-dimensional chromatin contacts and regulatory DNA accessibility at each position. Chromatin is DNA packaged with proteins inside the nucleus.

Chromatin forms loops that bring a regulatory region close to the gene it controls, even when they lie far apart in the linear DNA sequence. An open chromatin region is accessible to regulatory proteins, which gives the cell one way to control gene activity. Spatial coordinates matter because neighboring cells in a tissue can belong to different cell types and follow different gene expression programs.

To determine these coordinates, the authors fixed the tissue to a glass slide, ligated DNA fragments that had been in contact inside the nuclei, and passed two perpendicular sets of barcoded microchannels across the section. After sequencing, each barcode combination identifies the position associated with the DNA contacts and accessible regulatory regions.

The authors validated the method on adjacent mouse brain sections. They compared the contact maps with in situ Hi-C, a standard method for mapping chromatin contacts, and the open-chromatin maps with ATAC-seq, a method for identifying accessible chromatin. The results agreed with both independent measurements. This shows that the combined protocol can measure contacts and accessibility in the same sample while retaining the corresponding data. In brain tissue, the method distinguished chromatin loops associated with different neuronal types and anatomical regions.

In astrocytoma and glioblastoma samples, both types of brain tumor, Spatial-ATAC-Hi-C detected changes in DNA copy number and large structural rearrangements. The authors compared these results with whole-genome sequencing from adjacent sections. In a separate glioblastoma sample, they found spatially distinct groups of positions with different copy-number profiles. The contact and accessibility maps separated the positions into the same groups.

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Two limitations affect how these results should be interpreted. The spatial resolution remains multicellular because each position contains 3 to 21 cells. In aging tissue, the method could test whether age-related changes in DNA accessibility, long-range genomic contacts, and cellular composition occur in the same regions, but this paper contains no aging data.

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Sources
[1] nature.com
[2] t.me