Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

Science, Journal Year: 2022, Volume and Issue: 376(6594)

Published: May 12, 2022

Understanding gene function and regulation in homeostasis disease requires knowledge of the cellular tissue contexts which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen types from 16 donors 25 samples, generating a cross-tissue atlas 209,126 nuclei profiles, integrated across tissues, donors, laboratory with conditional variational autoencoder. Using resulting atlas, highlight shared tissue-specific features tissue-resident cell populations; identify that might contribute neuromuscular, metabolic, immune components monogenic diseases biological processes involved their pathology; determine modules underlie mechanisms for complex traits analyzed by genome-wide association studies.

Language: Английский

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scGPT: toward building a foundation model for single-cell multi-omics using generative AI

Nature Methods, Journal Year: 2024, Volume and Issue: 21(8), P. 1470 - 1480

Published: Feb. 26, 2024

Language: Английский

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hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data

Cell Reports Methods, Journal Year: 2023, Volume and Issue: 3(6), P. 100498 - 100498

Published: June 1, 2023

Biological systems are immensely complex, organized into a multi-scale hierarchy of functional units based on tightly regulated interactions between distinct molecules, cells, organs, and organisms. While experimental methods enable transcriptome-wide measurements across millions popular bioinformatic tools do not support systems-level analysis. Here we present hdWGCNA, comprehensive framework for analyzing co-expression networks in high-dimensional transcriptomics data such as single-cell spatial RNA sequencing (RNA-seq). hdWGCNA provides functions network inference, gene module identification, enrichment analysis, statistical tests, visualization. Beyond conventional RNA-seq, is capable performing isoform-level analysis using long-read data. We showcase from autism spectrum disorder Alzheimer's disease brain samples, identifying disease-relevant modules. directly compatible with Seurat, widely used R package demonstrate the scalability by dataset containing nearly 1 million cells.

Language: Английский

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Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure

Nature Cardiovascular Research, Journal Year: 2022, Volume and Issue: 1(3), P. 263 - 280

Published: March 16, 2022

Heart failure represents a major cause of morbidity and mortality worldwide. Single-cell transcriptomics have revolutionized our understanding cell composition associated gene expression. Through integrated analysis single-cell single-nucleus RNA-sequencing data generated from 27 healthy donors 18 individuals with dilated cardiomyopathy, here we define the failing human heart. We identify cell-specific transcriptional signatures age heart reveal emergence disease-associated states. Notably, cardiomyocytes converge toward common states, whereas fibroblasts myeloid cells undergo dramatic diversification. Endothelial pericytes display global shifts without changes in complexity. Collectively, findings provide comprehensive cellular transcriptomic landscape failure, type-specific programs states establish valuable resource for investigation failure.

Language: Английский

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Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis

Cell stem cell, Journal Year: 2020, Volume and Issue: 28(3), P. 472 - 487.e7

Published: Dec. 21, 2020

Regulation of hematopoiesis during human development remains poorly defined. Here we applied single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin (scATAC-seq) to over 8,000 immunophenotypic blood cells from fetal liver bone marrow. We inferred their differentiation trajectory identified three highly proliferative oligopotent progenitor populations downstream hematopoietic stem (HSCs)/multipotent progenitors (MPPs). Along this trajectory, observed opposing patterns accessibility that coincided with dynamic changes in the activity distinct lineage-specific transcription factors. Integrative analysis gene expression revealed extensive epigenetic but not transcriptional priming HSCs/MPPs prior lineage commitment. Finally, refined functionally validated sorting strategy achieved around 90% enrichment. Our study provides a useful framework future investigation developmental context pathologies regenerative medicine.

Language: Английский

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High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(12), P. 1503 - 1520.e8

Published: Nov. 10, 2022

Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune infiltration patterns, which has been linked to therapy sensitivity and resistance. However, full understanding of how phenotypes vary across different patient subgroups lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution integrating 1,283,972 single cells from 556 samples 318 patients 29 datasets, including our dataset capturing low mRNA content. We stratify into immune-deserted, B cell, T myeloid subtypes. Using bulk genomic clinical information, identify cellular components associated histology genotypes. then focus on analysis tissue-resident neutrophils (TRNs) uncover distinct subpopulations that acquire new functional properties in tissue microenvironment, providing evidence for plasticity TRNs. Finally, show a TRN-derived gene signature anti-programmed death ligand 1 (PD-L1) treatment failure.

Language: Английский

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Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Language: Английский

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Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(6), P. 346 - 362

Published: May 17, 2023

Language: Английский

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HypoMap—a unified single-cell gene expression atlas of the murine hypothalamus

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(10), P. 1402 - 1419

Published: Oct. 20, 2022

Language: Английский

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The scverse project provides a computational ecosystem for single-cell omics data analysis

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 41(5), P. 604 - 606

Published: April 10, 2023

Language: Английский

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