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Single cell transcriptomics technologies have vast potential in advancing our understanding of biology and disease. Here, Sarah Aldridge and Sarah Teichmann review the last decade of technological advancements in single-cell transcriptomics and highlight some of the recent discoveries enabled by this technology.

Sarah Teichmann, head of cellular genetics at the Wellcome Sanger Institute, reflects on the dawn of the single-cell genomics era and a pivotal decision that changed the course of her career.

A discussion of some of the challenges and promise of single-cell technology.

Human challenge studies with SARS-CoV-2 have shown changes in the innate and adaptive immune response. Here the authors are examining potential correlates of infection in virus challenged recipients by assessing baseline immune parameters and how this predicts virus control.

Nature Biotechnology asks a selection of researchers about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications.

As an ambitious project to map all the cells in the human body gets officially under way, Aviv Regev, Sarah Teichmann and colleagues outline some key challenges.

Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.

Transcriptomic and proteomic profiling of blood samples from individuals with COVID-19 reveals immune cell and hematopoietic progenitor cell alterations that are differentially associated with disease severity.

An evaluation framework isolates perturbation-specific effects in perturbation datasets.

A vascular cell atlas integrating single-cell data of 19 organs and tissues from 62 donors identifies angiotypic and organotypic characteristics of endothelial and mural cells.

Studies in mice show that effector T regulatory cells in the gut are most functional in the lamina propria, but this homeostatic niche is disrupted in inflammation, suggesting a spatial mechanism of tolerance to commensal microorganisms.

Wells et al. profile RNA and surface protein expression to describe dominant tissue-specific effects on immune cell composition and function across lineages in the human tissues across age.

Transcription factors (TFs) are essential for gene expression, but very little is known about the majority of human TFs. This Analysis article provides a manually curated repertoire of sequence-specific human TFs as a foundation for future research, and examines patterns of TF expression and conservation.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

A multiomic atlas of human embryonic joint and cranium development enables detailed analysis of bone and cartilage maturation.

Although most proteins contain multiple domains, nearly all folding studies so far have been of single domains in isolation. Here we consider the importance of interdomain cooperativity in protein folding and propose evolutionary mechanisms that prevent misfolding in multidomain proteins.

Here, Easter et al. generate a single-cell atlas of human periodontium including sulcular and junctional keratinocytes. Cell-cell communication analysis is used to predict keratinocyte-specific immune cell interactions.

A comprehensive multi-omics reference atlas of prenatal human skin shows that innate immune cells crosstalk with non-immune cells to perform pivotal roles in skin morphogenesis, including the formation of hair follicles.

A quantitative morphological framework for the human thymus reveals the establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions in fetal and paediatric thymic development.

The study provides a comprehensive transcriptomic atlas of the human gastrointestinal tract across the lifespan, highlighting inflammation-induced changes in epithelial stem cells that alter mucosal architecture and promote further inflammation.

This Roadmap presents and outlines the creation of the Human Liver Cell Atlas as a reference map and resource for the liver community, providing an overview of the steps needed to build the atlas, as well as outlining the major challenges and potential of this venture.

Single-cell transcriptomics and protein expression analyses of salivary glands and gingiva, along with the detection of infectious virus and virus-specific antibodies in saliva from SARS-CoV-2-infected individuals, support a potential role for the oral cavity in COVID-19 pathogenesis.

Here Sarah Teichmann and colleagues provide a Perspective on the exponential scaling of single-cell RNA-sequencing experiments over the last decade, commenting on the methodological developments that have underpinned the advances in this technology.

Single-cell and spatial transcriptomic analysis of eight human heart tissues reveals the cellular profiles and tissue architecture of niches including the cardiac conduction system, and a new tool, drug2cell, identifies drug target expression.

A human SARS-CoV-2 challenge study in individuals without previous exposure to the virus or vaccines provides detailed profiles of local and systemic epithelial and immune cell response dynamics over time and infection status.

Multi-Inflammatory Syndrome in Children (MIS-C) is a severe post-infectious presentation related to SARS-CoV-2 infection. Here authors used multi-omics approaches to characterise MIS-C cases and found increased CD95 and IL-18 signalling accompanying the expansion of TCR Vβ 21.3+ T cells.

Wesley et al. describe the developmental trajectories of human foetal liver cell types at single-cell resolution and generate bipotential hepatoblast organoids, which can serve as a new platform to investigate human liver development.

Age-specific differences upon SARS-CoV-2 infection are marked by emergence of goblet 2 inflammatory cells expressing antiviral interferon stimulating genes in paediatric nasal cultures, and basaloid-like cells with increased viral spread in cultures from older adults.

This Resource describes data, code and tools developed for the Human Reference Atlas and the Human BioMolecular Atlas Program for building and navigating a multiscale human atlas.

A single-cell atlas of human fetal bone marrow in healthy fetuses and fetuses with Down syndrome provides insight into developmental haematopoiesis in humans and the transcription and functional differences that occur in Down syndrome.

Single-cell transcriptomics reveals immune and stromal compartment remodeling, including the enrichment of unique populations of epithelial cells and CD4⁺ T cells, in asthmatic lungs

A computational pipeline enables differential V(D)J usage analysis and pseudotime trajectory inference from single-cell AIR sequencing.

Single-cell transcriptomic and phylogenetic analyses reveal new insights into the developmental origin and potential therapeutic targets for a particularly aggressive form of B-cell acute lymphoblastic leukemia in infants.

Clatworthy and colleagues examine adult nasal lymphoid tissues in response to SARS-CoV-2 infection. Longitudinal profiling reveals changes in barrier tissue to block viral entry beyond the epithelial cell layer and how tissue repair occurred after viral infection.

In mammalian cells, during transcription and replication, RNA:DNA hybrid structures known as R-loops can arise, posing as obstacles to replication fork progression. Here the authors reveal that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication associated DNA damage in cancer cells.

An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

The spike protein of the Omicron variant of SARS-CoV-2 has a higher affinity for ACE2 than Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic and vaccine-elicited neutralizing antibodies.

Maatz, Lindberg et al. identify molecular alterations and immune response changes in endomyocardial biopsies from patients with myocarditis after COVID-19 infection, after anti-COVID-19 vaccination or from non-COVID-related causes.

A large-scale analysis of DNA-bound transcription factors (TFs) shows how the presence of DNA markedly affects the landscape of TF interactions, and identifies composite motifs that are recognized by complexes of TFs rather than by individual ones.

Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.

A new multilevel clustering approach applied retrospectively to 13,000 transcriptomes of different tumors reveals a new diagnostic classification of childhood cancers, in some cases allowing a better prediction of disease outcomes.

Using single-cell and spatial transcriptomics, human embryonic limb development across space and time and the diversification and cross-species conservation of cells are demonstrated.

An analysis of single-cell transcriptomics datasets from different tissues shows that ACE2 and TMPRSS2 are co-expressed in respiratory, corneal and intestinal epithelial cell populations, and that respiratory expression of ACE2 is associated with genes involved in innate immunity.

The HOX gene cluster is responsible for anteroposterior axis patterning in an evolutionarily conserved manner. Here they examine HOX gene expression in human embryos and show that neural-crest derivatives retain the anatomical HOX code of their origin while also adopting the code of their destination.