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PgmNr 306: Spatially-resolved single-cell chromatin accessibility in the adult mouse brain.

C.A. Thornton 1; A. Mishra 2; A.P. Barnes 2; B.J. O'Roak 1; A.C. Adey 1,2,3

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1) Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR.; 2) Knight Cardiovascular Institute, Portland, OR; 3) Knight Cancer Institute, Portland, OR

The adult brain is a complex network of neuronal and non-neuronal cell type interactions with spatially oriented regions that accomplish a near infinite variety of computational tasks. The mammalian cerebral cortex in particular carries out higher cognitive processes such as vision, motor function and hearing, and is characterized by six spatially distinct layers comprised of unique populations of neuronal and non-neuronal cell types. The advent of single-cell omics technologies has allowed for the characterization of individual cell epigenomic states in heterogeneous tissues. However, our ability to characterize how cells vary by spatial orientation is limited. In this study we introduce a novel technique for the characterization of single-cell epigenomic landscapes while maintaining the spatially-resolved origin of the profiled cells. We focus on the somatosensory cortex of adult mice, in order to demonstrate the gradient of epigenetic states of cells from lower to upper cortical layers. Spatially-resolved Single-cell Combinatorial Indexed Assay-for-Transposase-Accessible-Chromatin using sequencing (sci-ATAC-seq) was used to generate 19,896 single-cell chromatin accessibility profiles from spatially oriented microbiopsies from upper cortex, lower cortex and whole mouse brains. We utilized topic-based clustering to identify major neuronal and non-neuronal cell types, and further resolved epigenetic gradients based on upper and lower cortical layer spatial identity. Additionally, we have applied this novel technique to stroke model mice and demonstrate the ability of spatially resolved sci-ATAC-seq to reveal chromatin remodeling that occurs in a spatial gradient extending from the infarct. We believe that this novel method can be utilized across many tissues in order to fully characterize the spatial epigenomic landscapes of complex tissues.