Prefrontal Cortex Louise A. Huuki-Myers1, Abby Spangler1, Nicholas J. Eagles1, Kelsey D. Montgomery1, Sang Ho Kwon1,2, Boyi Guo3, Melissa Grant-Peters4,5, Heena R. Divecha1, Madhavi Tippani1, Chaichontat Sriworarat1,2, Annie B. Nguyen1, Prashanthi Ravichandran6, Matthew N. Tran1, Arta Seyedian1, PsychENCODE consortium, Thomas M. Hyde1,7,8, Joel E. Kleinman1,7, Alexis Battle6,9,10,11 , Stephanie C. Page1, Mina Ryten4,5,12, Stephanie C. Hicks3,11, Keri Martinowich1,2,7, Leonardo Collado-Torres1*, Kristen R. Maynard1,2,7* 1. Lieber Institute for Brain Development, 2. The Solomon H. Snyder Department of Neuroscience Johns Hopkins School of Medicine (JHSM), 3. Department of Biostatistics Johns Hopkins Bloomberg School of Public Health, 4. Genetics and Genomic Medicine Great Ormond Street Institute of Child Health University College London, 5. Aligning Science Across Parkinson’s Collaborative Research Network, 6. Department of Biomedical Engineering JHSM, 7. Department of Psychiatry and Behavioral Sciences JHSM, 8. Department of Neurology JHSM, 9. Department of Computer Science JHU, 10. Department of Genetic Medicine JHSM, 11. Malone Center for Engineering in Healthcare JHU, 12. NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Overview Acknowledgements Identification of Cell Populations Across Spatial Domains Methods DE Genes in Spatial Domains Maynard et al., Nat Neurosci, 2021, 10.1038/s41593-020-00787-0 Zhao et al., Nat BioTech, 2021, 10.1038/s41587-021-00935-2 Emani et al, 2022, (syn30106435) 10.7303/syn4921369 snRNA-seq Identification of Data-Driven Spatial Domains Paired Single Nucleus RNA-seq Sp9 D1 is enriched for CLDN5: vascular domain (endothelial cells) Pairwise DE for Layer 1 sub-domains • Spatially registered nuclei on to classic layers reduces dataset to 12 layer associated cell types • Spatial registration on finer resolution novel domains may reveal additional information about cell type clusters k = number of domains s = domain number Identified 29 fine resolution clusters across 70k nuclei Access this Dataset Assay n Number of Samples Number of Donors 10x Visium 113,927 spots 30 10 snRNA-seq 77,604 nuclei (2661,5911) 19 10 Spatial Data Shiny App snRNA-seq on iSEE App BayesSpace: spatially-aware unsupervised clustering Spk Ds • K = 2: white matter vs. grey matter • K = 9: classic histological layers • K = 16: laminar with 2+ domains per histological layer 1 2 logcounts min > 0 CLDN5 1 2 3 logcounts min > 0 1 2 3 logcounts min > 0 ! Spatially resolved transcriptomics enables analysis of molecular organization of the human DLPFC ! Unbiased spatial domains, identified with 10x Visium data and un-supervised clustering, look beyond classic histological layers ! Integration with single nucleus RNA-sequencing data revealed distinct cell type compositions and cell-cell interactions within spatial domains ! Enrichment analysis link genes associated with neuropsychiatric disorders to discrete spatial domains. ! The research results and integrated datasets are available to the scientific community at research.libd.org/spatialDLPFC/ & via the spatialLIBD BioConductor Package preprint SpatialDLPFC Interactive Websites SpatialLIBD R Package & Data Download Poster speakerdeck.com/ lahuuki Annotation Confidence X - high * - low Cell2location Tangram Sp09D01 ~ L1 Sp09D02 ~ L1 Sp09D03 ~ L2 Sp09D05 ~ L3 Sp09D08 ~ L4 Sp09D04 ~ L5 Sp09D07 ~ L6 Sp09D06 ~ WM Sp09D09 ~ WM Sp09D01 ~ L1 Sp09D02 ~ L1 Sp09D03 ~ L2 Sp09D05 ~ L3 Sp09D08 ~ L4 Sp09D04 ~ L5 Sp09D07 ~ L6 Sp09D06 ~ WM Sp09D09 ~ WM 0.00 0.25 0.50 0.75 1.00 Annotated Layer Proportion of Counts Cell Type Astro EndoMural Micro Oligo OPC Excit_L2_3 Excit_L3 Excit_L3_4_5 Excit_L4 Excit_L5 Excit_L5_6 Excit_L6 Inhib Spot Deconvolution Astro EndoMural Micro Oligo OPC Excit_L2/3 Excit_L3 Excit_L3/4/5 Excit_L4 Excit_L5 Excit_L5/6 Excit_L6 Inhib Astro EndoMural Micro Oligo OPC Excit_L2/3 Excit_L3 Excit_L3/4/5 Excit_L4 Excit_L5 Excit_L5/6 Excit_L6 Inhib Cell2location Tangram Spatial Registration of Neuropsychiatric Data Sets Spatially Map Disease Ligand Receptor Interactions PsychENCODE Consortium * co-corresponding authors Presenter Louise Huuki-Myers Staff Scientist at LIBD @lahuuki lahuuki.github.io Tutorial: Spatial Registration C D
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