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New study spatially maps chromatin accessibility in embryos, brains, and more

Written by Miyako Rogers, Science Writer

In a recent study published in Nature, researchers have uncovered the spatial epigenetic information of mouse embryos, mouse brains, human brains, and tonsils. To achieve this, researchers developed a new method combining next-generation sequencing techniques with microfluidics and bacterial transposition. Researchers mapped tissue region-specific epigenetic landscapes, revealed novel gene regulators, and identified the formation and specification of distinct functional areas in the brain. 

New Spatial Mapping Technique: Spatial-ATAC-seq

The advantage of spatial transcriptomics over single-cell sequencing is that tissue structure and integrity is preserved. Therefore, you can see the genetic changes of individual cells in the right spatial context. Whilst mapping out gene expression with spatial transcriptomics has been done before, this study spatially mapped epigenetic states instead, specifically chromatin accessibility.

To do so, a new approach called spatial-ATAC-seq was developed (spatial assay for transposase-accessible chromatin using sequencing). First, specific DNA oligomers were inserted into accessible chromatin by Tn5 transposition (Tn5 is a bacterial transposon). Next different barcodes (DNA fragments) with linkers were introduced using microchannels and were ligated to the end of the DNA oligomers, creating a spatial barcoding scheme. The tissue was then imaged so that spatially barcoded chromatin correlated with tissue morphology. Then, reverse cross-linking released the barcodes, which were amplified by PCR and sequenced.

Figure 1 ¦ Clustering analysis of chromatin accessibility in mouse embryo. Clusters were overlaid on top of the tissue image revealing that chromatin accessibility precisely matches anatomical regions.

Mapping the tissues

In mouse embryos (Figure 1), spatial mapping of chromatin accessibility uncovered the epigenetic landscape of organogenesis, as well as when and where organs developed in the very early stages. Researchers also identified specific chromatin regulatory elements, as well as the SOX6 gene as a regulator in the development of the central nervous system. In the mouse and human brain, researchers revealed the intricate arealization of brain regions: The formation and specification of distinct functional areas in the brain. In human tonsils, they mapped out the epigenetic dynamics of B cell and macrophage activation.

Future directions and implications

Spatial transcriptomics is a new and emerging technology, and every week more and more studies come out, further developing and advancing this technology, expanding its capabilities and uses. This study is the first of its kind to map epigenetic changes, particularly in such complex organs. In the embryo, further studies could elucidate the role epigenetics plays in developmental biology. In the brain, epigenetics is an emerging field of study in the context of neurodegenerative diseases.

Future studies could investigate the role epigenetic modifications play in the pathology of these diseases and perhaps discover new treatment targets. Further studies into the tonsils, and other lymph organs, could also uncover new insights into how epigenetics impacts the immune system, both in normal physiology and in the context of autoimmune diseases.

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Spatial Transcriptomics