A decade of molecular cell atlases

Quake, Stephen R.

doi:10.1016/j.tig.2022.01.004

Cited by 33 publications

(25 citation statements)

References 52 publications

(49 reference statements)

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“…Single-cell RNA sequencing (scRNA-seq) quantifies gene expression in individual cell types, as opposed to the tissue-wide measurements obtained from conventional "bulk" RNA-seq. Applications range from broad "cell atlas'' projects 1,2 to studies of specific diseases such as Alzheimer's [3][4][5] . When dissociation of intact single cells is difficult, as with frozen nervous tissue samples, researchers often instead use single-nucleus sequencing (snucRNA-seq), where nuclei are isolated from cell lysate.…”

Section: Introductionmentioning

confidence: 99%

Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments

Chamberlin

Lee

Marth

et al. 2022

Preprint

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The capacity for nuclear RNA measurements to recapitulate results from whole cells is essential to the utility of single-nucleus RNA-seq. While early studies argued that nuclear samples could yield comparable results to single-cell RNA-seq, both assays have since been appreciated to be subject to certain systematic biases. These include differences in the localization and capture mode of spliced and unspliced RNAs. However, variability in these biases across cell types has received limited direct attention. Here, we describe the contrasting effects of mRNA and pre-mRNA sampling on inter-assay compatibility among cell types of the cortex, their mechanisms, and their impact on the generalizability of a recently published normalization method. We show that baseline similarity is comparatively high in cortex cell types, and is moderated both by gene length bias in pre-mRNAs and by inherent differences in mRNA abundances, the balance of which varies considerably across cell types. These factors cause inconsistent performance of the normalization method, which emphasizes mRNA measurements by downweighting pre-mRNA measurements according to gene length. Critically, the high baseline similarity of single-cell and nucleus RNA-seq in cortex depends on the inclusion of pre-mRNA signal, but pre-mRNA abundances alone are not strongly predictive of mRNA abundances. This is important to problems such as bulk sample deconvolution. Broadly, our analysis provides a mechanistic explanation for variation in assay similarity across cell types and argues for the potential application of post hoc normalization approaches as an alternative route to improved biological interpretation.

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Section: Introductionmentioning

confidence: 99%

Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments

Chamberlin

Lee

Marth

et al. 2022

Preprint

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“…Atlases for a set of human and mouse tissue types have been constructed using various data modalities, such as in situ hybridization, single-cell RNA-sequencing, histology, and spatial gene expression (Lein et al, 2007;Sunkin et al, 2012;Rozenblatt-Rosen et al, 2017;Quake, 2022;Shekhar and Sanes, 2021). However, comprehensive atlases using the most modern spatial gene expression profiling methods have yet to be established.…”

Section: Atlas Building Objectivementioning

confidence: 99%

Optimizing the design of spatial genomic studies

Jones

Cai

et al. 2023

Preprint

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Spatially-resolved genomic technologies have shown promise for studying the relationship between the structural arrangement of cells and their functional behavior. While numerous sequencing and imaging platforms exist for performing spatial transcriptomics and spatial proteomics profiling, these experiments remain expensive and labor-intensive. Thus, when performing spatial genomics experiments using multiple tissue slices, there is a need to select the tissue cross sections that will be maximally informative for the purposes of the experiment. In this work, we formalize the problem of experimental design for spatial genomics experiments, which we generalize into a problem class that we callstructured batch experimental design. We propose approaches for optimizing these designs in two types of spatial genomics studies: one in which the goal is to construct a spatially-resolved genomic atlas of a tissue and another in which the goal is to localize a region of interest in a tissue, such as a tumor. We demonstrate the utility of these optimal designs, where each slice is a two-dimensional plane, on several spatial genomics datasets.

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“…[64][65][66] However, a limitation of synovial fluid is that it does not include all representative tissue populations, such as stroma and synovial tissue fibroblasts and macrophages, which are thought to play pivotal roles in the balance between tissue inflammation and resolution 57 67 68 In rheumatoid arthritis (RA), the development of minimally invasive, ultrasound guided synovial biopsy techniques, combined with significant advances in technology, including the ability to perform multimodal cellular and spatial tissue analysis at the single cell level, has led to a paradigm shift in our understanding of tissue-based mechanisms of disease. [69][70][71] For example, single cell profiling studies of specific tissue resident, effector cell populations have led to novel insights into the phenotypic and functional diversity of synovial tissue cells, while at the same time identifying novel and tractable therapeutic targets. [72][73][74] Furthermore, distinct molecular and cellular signatures have been found to associate with histologically defined synovial tissue pathotypes.…”

Section: Reviewmentioning

confidence: 99%

Towards molecular-pathology informed clinical trials in childhood arthritis to achieve precision medicine in juvenile idiopathic arthritis

et al. 2022

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In childhood arthritis, collectively known as Juvenile idiopathic arthritis (JIA), the rapid rise of available licensed biological and targeted small molecule treatments in recent years has led to improved outcomes. However, real-world data from multiple countries and registries show that despite a large number of available drugs, many children and young people continue to suffer flares and experience significant periods of time with active disease for many years. More than 50% of young people with JIA require ongoing immune suppression well into adult life, and they may have to try multiple different treatments in that time. There are currently no validated tools with which to select specific treatments, nor biomarkers of response to assist in such choices, therefore, current management uses essentially a trial-and-error approach. A further consequence of recent progress is a reducing pool of available children or young people who are eligible for new trials. In this review we consider how progress towards a molecular based approach to defining treatment targets and informing trial design in JIA, combined with novel approaches to clinical trials, could provide strategies to maximise discovery and progress, in order to move towards precision medicine for children with arthritis.

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A decade of molecular cell atlases

Cited by 33 publications

References 52 publications

Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments

Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments

Optimizing the design of spatial genomic studies

Towards molecular-pathology informed clinical trials in childhood arthritis to achieve precision medicine in juvenile idiopathic arthritis

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