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Conserved cell types with divergent features in human versus mouse cortex.

ABSTRACT: Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

SUBMITTER: Hodge RD

PROVIDER: S-EPMC6919571 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Conserved cell types with divergent features in human versus mouse cortex.

Hodge Rebecca D RD Bakken Trygve E TE Miller Jeremy A JA Smith Kimberly A KA Barkan Eliza R ER Graybuck Lucas T LT Close Jennie L JL Long Brian B Johansen Nelson N Penn Osnat O Yao Zizhen Z Eggermont Jeroen J Höllt Thomas T Levi Boaz P BP Shehata Soraya I SI Aevermann Brian B Beller Allison A Bertagnolli Darren D Brouner Krissy K Casper Tamara T Cobbs Charles C Dalley Rachel R Dee Nick N Ding Song-Lin SL Ellenbogen Richard G RG Fong Olivia O Garren Emma E Goldy Jeff J Gwinn Ryder P RP Hirschstein Daniel D Keene C Dirk CD Keshk Mohamed M Ko Andrew L AL Lathia Kanan K Mahfouz Ahmed A Maltzer Zoe Z McGraw Medea M Nguyen Thuc Nghi TN Nyhus Julie J Ojemann Jeffrey G JG Oldre Aaron A Parry Sheana S Reynolds Shannon S Rimorin Christine C Shapovalova Nadiya V NV Somasundaram Saroja S Szafer Aaron A Thomsen Elliot R ER Tieu Michael M Quon Gerald G Scheuermann Richard H RH Yuste Rafael R Sunkin Susan M SM Lelieveldt Boudewijn B Feng David D Ng Lydia L Bernard Amy A Hawrylycz Michael M Phillips John W JW Tasic Bosiljka B Zeng Hongkui H Jones Allan R AR Koch Christof C Lein Ed S ES

Nature 20190821 7772

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex sing ...[more]

PMID: 31435019

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Project description:Background: Understanding how tumors subvert immune destruction is essential to the development of cancer immunotherapies. New evidence suggests that tumors limit anti-tumor immunity by exploiting transcriptional programs that regulate intratumoral trafficking and accumulation of effector cells. Here, we investigated the gene expression profiles that distinguish immunologically "cold" and "hot" tumors across diverse tumor types. Methods: RNAseq profiles of tumors (n = 8,920) representing 23 solid tumor types were analyzed using immune gene signatures that quantify CD8+ T cell abundance. Genes and pathways associated with a low CD8+ T cell infiltration profile (CD8-Low) were identified by correlation, differential expression, and statistical ranking methods. Gene subsets were evaluated in immunotherapy treatment cohorts and functionally characterized in cell lines and mouse tumor models. Results: Among different cancer types, we observed highly significant overlap of genes enriched in CD8-Low tumors, which included known immunomodulatory genes (e.g., BMP7, CMTM4, KDM5B, RCOR2) and exhibited significant associations with Wnt signaling, neurogenesis, cell-cell junctions, lipid biosynthesis, epidermal development, and cancer-testis antigens. Analysis of mutually exclusive gene clusters demonstrated that different transcriptional programs may converge on the T cell-cold phenotype as well as predict for response and survival of patients to Nivo treatment. Furthermore, we confirmed that a top-ranking candidate belonging to the TGF-? superfamily, BMP7, negatively regulates CD8+ T cell abundance in immunocompetent murine tumor models, with and without anti-PD-L1 treatment. Conclusions: This study presents the first evidence that solid tumors of diverse anatomical origin acquire conserved transcriptional alterations that may be operative in the T cell-cold state. Our findings demonstrate the potential clinical utility of CD8-Low tumor-associated genes for predicting patient immunotherapy outcomes and point to novel mechanisms with potential for broad therapeutic exploitation.

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Conserved cell types with divergent features in human versus mouse cortex.

Publications

Conserved cell types with divergent features in human versus mouse cortex.

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