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Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells.

ABSTRACT: Syncytial skeletal muscle cells contain hundreds of nuclei in a shared cytoplasm. We investigated nuclear heterogeneity and transcriptional dynamics in the uninjured and regenerating muscle using single-nucleus RNA-sequencing (snRNAseq) of isolated nuclei from muscle fibers. This revealed distinct nuclear subtypes unrelated to fiber type diversity, previously unknown subtypes as well as the expected ones at the neuromuscular and myotendinous junctions. In fibers of the Mdx dystrophy mouse model, distinct subtypes emerged, among them nuclei expressing a repair signature that were also abundant in the muscle of dystrophy patients, and a nuclear population associated with necrotic fibers. Finally, modifications of our approach revealed the compartmentalization in the rare and specialized muscle spindle. Our data identifies nuclear compartments of the myofiber and defines a molecular roadmap for their functional analyses; the data can be freely explored on the MyoExplorer server ( https://shiny.mdc-berlin.de/MyoExplorer/ ).

SUBMITTER: Kim M

PROVIDER: S-EPMC7732842 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells.

Kim Minchul M Franke Vedran V Brandt Bettina B Lowenstein Elijah D ED Schöwel Verena V Spuler Simone S Akalin Altuna A Birchmeier Carmen C

Nature communications 20201211 1

Syncytial skeletal muscle cells contain hundreds of nuclei in a shared cytoplasm. We investigated nuclear heterogeneity and transcriptional dynamics in the uninjured and regenerating muscle using single-nucleus RNA-sequencing (snRNAseq) of isolated nuclei from muscle fibers. This revealed distinct nuclear subtypes unrelated to fiber type diversity, previously unknown subtypes as well as the expected ones at the neuromuscular and myotendinous junctions. In fibers of the Mdx dystrophy mouse model, ...[more]

PMID: 33311457

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Project description:Skeletal muscle, the largest human organ by weight, is relevant to several polygenic metabolic traits and diseases including type 2 diabetes (T2D). Identifying genetic mechanisms underlying these traits requires pinpointing the relevant cell types, regulatory elements, target genes, and causal variants. Here, we used genetic multiplexing to generate population-scale single nucleus (sn) chromatin accessibility (snATAC-seq) and transcriptome (snRNA-seq) maps across 287 frozen human skeletal muscle biopsies representing 456,880 nuclei. We identified 13 cell types that collectively represented 983,155 ATAC summits. We integrated genetic variation to discover 6,866 expression quantitative trait loci (eQTL) and 100,928 chromatin accessibility QTL (caQTL) (5% FDR) across the five most abundant cell types, cataloging caQTL peaks that atlas-level snATAC maps often miss. We identified 1,973 eGenes colocalized with caQTL and used mediation analyses to construct causal directional maps for chromatin accessibility and gene expression. 3,378 genome-wide association study (GWAS) signals across 43 relevant traits colocalized with sn-e/caQTL, 52% in a cell-specific manner. 77% of GWAS signals colocalized with caQTL and not eQTL, highlighting the critical importance of population-scale chromatin profiling for GWAS functional studies. GWAS-caQTL colocalization showed distinct cell-specific regulatory paradigms. For example, a C2CD4A/B T2D GWAS signal colocalized with caQTL in muscle fibers and multiple chromatin loop models nominated VPS13C, a glucose uptake gene. Sequence of the caQTL peak overlapping caSNP rs7163757 showed allelic regulatory activity differences in a human myocyte cell line massively parallel reporter assay. These results illuminate the genetic regulatory architecture of human skeletal muscle at high-resolution epigenomic, transcriptomic, and cell state scales and serve as a template for population-scale multi-omic mapping in complex tissues and traits.

Dataset Information

Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells.

Publications

Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells.

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