A5016746163- Single-cell and spatial transcriptomics
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- COVID-19 Clinical Research Studies
- Cancer Cells and Metastasis
- Cancer-related gene regulation
- Cell Image Analysis Techniques
- Immune cells in cancer
- Neonatal Respiratory Health Research
- Cancer-related molecular mechanisms research
- Cannabis and Cannabinoid Research
- RNA modifications and cancer
- SARS-CoV-2 and COVID-19 Research
- Eosinophilic Esophagitis
- Neuroscience and Neuropharmacology Research
- Infant Nutrition and Health
- Computational Drug Discovery Methods
- Genomics and Chromatin Dynamics
- Advanced Proteomics Techniques and Applications
- Immune responses and vaccinations
- Neuroinflammation and Neurodegeneration Mechanisms
- Gene expression and cancer classification
- Mass Spectrometry Techniques and Applications
- Digital Imaging in Medicine
- COVID-19 Impact on Reproduction
ETH Zurich
2022-2025
University of Cambridge
2017-2022
Wellcome/MRC Cambridge Stem Cell Institute
2022
Cancer Research UK
2021-2022
European Bioinformatics Institute
2016-2021
Cancer Research UK Cambridge Center
2017-2019
University of Bonn
2014-2018
Johannes Gutenberg University Mainz
2015
University Medical Center of the Johannes Gutenberg University Mainz
2015
Normalization of single-cell RNA sequencing data is necessary to eliminate cell-specific biases prior downstream analyses. However, this not straightforward for noisy where many counts are zero. We present a novel approach expression values summed across pools cells, and the used normalization. Pool-based size factors then deconvolved yield cell-based factors. Our deconvolution outperforms existing methods accurate normalization in simulated data. Similar behavior observed real data,...
Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T B lymphocyte antigen receptor analyses over 780,000 peripheral mononuclear from a cross-sectional cohort 130 patients with varying severities COVID-19. identified expansion nonclassical monocytes expressing complement transcripts (CD16
Characterising the hierarchy of mammary epithelial cells (MECs) and how they are regulated during adult development is important for understanding breast cancer arises. Here we report use single-cell RNA sequencing to determine gene expression profile MECs across four developmental stages; nulliparous, mid gestation, lactation post involution. Our analysis 23,184 identifies 15 clusters, few which could be fully characterised by a single marker gene. We argue instead that cells-especially in...
Abstract Barcode swapping results in the mislabelling of sequencing reads between multiplexed samples on patterned flow-cell Illumina machines. This may compromise validity numerous genomic assays; however, severity and consequences barcode remain poorly understood. We have used two statistical approaches to robustly quantify fraction swapped plate-based single-cell RNA-sequencing datasets. found that approximately 2.5% were mislabelled HiSeq 4000, which is lower than previous reports....
Objective Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology organism behaviour. Colonic sensory neurons activate reflex pathways give rise to conscious sensation, but diversity division function within these is poorly understood. The identification signalling contributing visceral sensation constrained by a paucity molecular markers. Here we address this comprehensive transcriptomic profiling unsupervised clustering individual...
Abstract In the past decade, single-cell transcriptomics has helped to uncover new cell types and states led construction of a cellular compendium health disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils—elusive granulocytes that are implicated in plethora human pathologies 1–5 —are among these uncharted types. The heterogeneity eosinophils gene programs underpin their pleiotropic functions poorly understood. Here we provide...
Detecting the targets of drugs and other molecules in intact cellular contexts is a major objective drug discovery biology more broadly. Thermal proteome profiling (TPP) pursues this aim at proteome-wide scale by inferring target engagement from its effects on temperature-dependent protein denaturation. However, key challenge TPP statistical analysis measured melting curves with controlled false rates high coverage detection power. We present nonparametric response (NPARC), method for based...
Abstract It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little known about loss-of-function (LOF) concomitant mutations affect progenitor cell state. Here we demonstrate time-resolved single-cell profiling genetically engineered mouse models before formation can address this challenge. We found that perturbing Brca1/p53 in induces...
Abstract Under normal conditions, the most significant expansion and differentiation of adult mammary gland occurs in response to systemic reproductive hormones during pregnancy lactation enable milk synthesis secretion sustain offspring. However, human tissue remodelling that takes place remains poorly understood due challenge acquiring samples. We report here single-cell transcriptomic analysis 110,744 viable breast cells isolated from or non-lactating tissue, nine seven donors,...
Abstract Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A , as a LUSC oncogene. Analysis cancer genomics datasets revealed to be upregulated in but not adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels vitro vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At molecular level found is transcriptionally...
Abstract Sequencing-based spatial transcriptomics (ST) methods allow unbiased capturing of RNA molecules at barcoded spots, charting the distribution and localization cell types transcripts across a tissue. While coarse resolution these techniques is considered disadvantage, we argue that inherent proximity transcriptomes captured on spots can be leveraged to reconstruct cellular networks. To this end, developed ISCHIA (Identifying Spatial Co-occurrence in Healthy InflAmed tissues),...
Abstract The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling over 800,000 peripheral blood mononuclear cells from a cohort 130 patients COVID-19. Our cohort, three UK centres, spans spectrum clinical presentations disease...
Abstract Cells collectively determine biological functions by communicating with each other—both through direct physical contact and secreted factors. Consequently, the local microenvironment of a cell influences its behavior, gene expression, cellular crosstalk. Disruption this causes reciprocal changes in those features, which can lead to development progression diseases. Hence, assessing transcriptome while simultaneously capturing spatial relationships cells within tissue provides highly...
Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Va (FVa). Using whole blood RNAseq scRNAseq of peripheral mononuclear cells, we find that FV mRNA expressed leukocytes, identify neutrophils, monocytes, T regulatory cells as sources increased hospitalized patients with COVID-19. Proteomic analysis confirms circulating neutrophils severe COVID-19, immunofluorescence microscopy identifies lung-infiltrating leukocytes COVID-19 lung...
Astrocytes, key regulators of brain homeostasis, interact with neighboring glial cells, neurons and the vasculature through complex processes involving different signaling pathways. It is not entirely clear how these interactions change in ageing which factors influence astrocyte ageing. Here, we investigate role endocannabinoid signaling, because it an important modulator neuron functions, as well We demonstrate that mice a specific deletion CB1 receptors on GABAergic (GABA-Cnr1-/- mice),...
Abstract Barcode swapping results in the mislabeling of sequencing reads between multiplexed samples on new patterned flow cell Illumina machines. This may compromise validity numerous genomic assays, especially for single-cell studies where many are routinely together. The severity and consequences barcode transcriptomic remain poorly understood. We have used two statistical approaches to robustly quantify fraction swapped each plate-based RNA datasets. found that approximately 2.5% were...
Abstract Findings from epidemiological studies suggest that breast cancer risk is influenced by parity in an age-dependent manner. However, human mammary tissue remodelling takes place during pregnancy and lactation remain little understood due to the challenge of acquiring samples. Here, we present approach overcome this using single-cell RNA sequencing examine viable primary epithelial cells isolated milk compared resting, non-lactating tissue. Thereby, determined separate tissue, largely...
Spatial transcriptomics techniques are able to chart the distribution and localization of cell types RNA molecules across a tissue. Here, we generated matched sequencing-based (Visium) hybridization-based (Molecular Cartography) spatial data human IBD samples. We then developed ISCHIA (Identifying Co-occurrence in Healthy InflAmed tissues), computational framework analyze co-occurrence transcript species tissue environment. revealed tightly associated cellular networks, ligand-receptor...
Abstract Detecting the targets of drugs and other molecules in intact cellular contexts is a major objective drug discovery biology more broadly. Thermal proteome profiling (TPP) pursues this aim at proteome-wide scale by inferring target engagement from its effects on temperature-dependent protein denaturation. However, key challenge TPP statistical analysis measured melting curves with controlled false rates high coverage detection power. We present non-parametric response (NPARC), method...
Supplementary materials. This file contains a justification of the choice pooling strategy (Section 1), discussion how to resolve linear dependencies 2), details on clustering algorithm 3), description high-coverage simulations 4), an outline computational complexity deconvolution 5), and offset/covariate method used assess normalization accuracy real data 6). It also Figures S1â S7 Tables S1 S2. (560 KB PDF)
Abstract The spatial organization of cells within tissues is tightly linked to their biological function. Yet, methods probe the entire transcriptome multiple native tissue microenvironments at single cell resolution are lacking. Here, we introduce spheresequencing, a method that enables transcriptomic characterization spatially distinct niches. Sphere-sequencing mouse metastatic liver revealed previously uncharacterized zonated genes and ligand-receptor interactions enriched in different...