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Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4⁺ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH⁺ CD8⁺ T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.

SUBMITTER: Perez RK

PROVIDER: S-EPMC9297655 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.

Perez Richard K RK Gordon M Grace MG Subramaniam Meena M Kim Min Cheol MC Hartoularos George C GC Targ Sasha S Sun Yang Y Ogorodnikov Anton A Bueno Raymund R Lu Andrew A Thompson Mike M Rappoport Nadav N Dahl Andrew A Lanata Cristina M CM Matloubian Mehrdad M Maliskova Lenka L Kwek Serena S SS Li Tony T Slyper Michal M Waldman Julia J Dionne Danielle D Rozenblatt-Rosen Orit O Fong Lawrence L Dall'Era Maria M Balliu Brunilda B Regev Aviv A Yazdany Jinoos J Criswell Lindsey A LA Zaitlen Noah N Ye Chun Jimmie CJ

Science (New York, N.Y.) 20220408 6589

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4<sup>+</sup> T cells that correlated with monocyte ISG expression, ...[more]

PMID: 35389781

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Project description:BackgroundOne of evolution's most important achievements is the development and radiation of multicellular organisms with different types of cells. Complex multicellularity has evolved several times in eukaryotes; yet, in most lineages, an investigation of its molecular background is considerably challenging since the transition occurred too far in the past and, in addition, these lineages evolved a large number of cell types. However, for volvocine green algae, such as Volvox carteri, multicellularity is a relatively recent innovation. Furthermore, V. carteri shows a complete division of labor between only two cell types - small, flagellated somatic cells and large, immotile reproductive cells. Thus, V. carteri provides a unique opportunity to study multicellularity and cellular differentiation at the molecular level.ResultsThis study provides a whole transcriptome RNA-Seq analysis of separated cell types of the multicellular green alga V. carteri f. nagariensis to reveal cell type-specific components and functions. To this end, 246 million quality filtered reads were mapped to the genome and valid expression data were obtained for 93% of the 14,247 gene loci. In the subsequent search for protein domains with assigned molecular function, we identified 9435 previously classified domains in 44% of all gene loci. Furthermore, in 43% of all gene loci we identified 15,254 domains that are involved in biological processes. All identified domains were investigated regarding cell type-specific expression. Moreover, we provide further insight into the expression pattern of previously described gene families (e.g., pherophorin, extracellular matrix metalloprotease, and VARL families). Our results demonstrate an extensive compartmentalization of the transcriptome between cell types: More than half of all genes show a clear difference in expression between somatic and reproductive cells.ConclusionsThis study constitutes the first transcriptome-wide RNA-Seq analysis of separated cell types of V. carteri focusing on gene expression. The high degree of differential expression indicates a strong differentiation of cell types despite the fact that V. carteri diverged relatively recently from its unicellular relatives. Our expression dataset and the bioinformatic analyses provide the opportunity to further investigate and understand the mechanisms of cell type-specific expression and its transcriptional regulation.

Dataset Information

Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.

Publications

Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.

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