A5036798094- Cancer Genomics and Diagnostics
- Cancer Cells and Metastasis
- Molecular Biology Techniques and Applications
- Genomic variations and chromosomal abnormalities
- Bioinformatics and Genomic Networks
- Genetic factors in colorectal cancer
- Gene expression and cancer classification
- Single-cell and spatial transcriptomics
- Digestive system and related health
- Acute Myeloid Leukemia Research
- Zebrafish Biomedical Research Applications
- Gene Regulatory Network Analysis
- Chromatin Remodeling and Cancer
- Pancreatic function and diabetes
- Machine Learning in Bioinformatics
- Wnt/β-catenin signaling in development and cancer
- Cardiac, Anesthesia and Surgical Outcomes
- PI3K/AKT/mTOR signaling in cancer
- Genomics and Rare Diseases
- Microbial Natural Products and Biosynthesis
- Pancreatitis Pathology and Treatment
- Protein Degradation and Inhibitors
- Enhanced Recovery After Surgery
- Pancreatic and Hepatic Oncology Research
- Hemoglobinopathies and Related Disorders
John Radcliffe Hospital
2018-2025
University of Oxford
2018-2025
MRC Weatherall Institute of Molecular Medicine
2017-2025
Royal College of Surgeons in Ireland
2024
Cancer Research UK
2013-2022
University of Cambridge
2012-2022
Institute of Molecular Medicine
2018-2022
Cancer Research UK Cambridge Center
2022
Ottawa Hospital Research Institute
2020
Ottawa Hospital
2020
Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial mesenchymal progenitor populations programs linked key morphogenetic milestones. describe principles crypt-villus axis formation; neural, vascular, morphogenesis, immune population developing gut. differentiation hierarchies fibroblast myofibroblast subtypes...
Limiting Tumor Initiation What is the competitive advantage of cells with frequently occurring mutations during tumor development? Vermeulen et al. (p. 995 ; see Perspective by Bozic and Nowak ) quantified advantages Apc -loss, Kras activation, P53 mutation initiation in mouse intestine. The conferred only a limited clonal advantage. Indeed, many mutated stem were stochastically replaced wild-type cells, helping to limit initiation.
During the lifetime of a fermenter culture, soil bacterium S. coelicolor undergoes major metabolic switch from exponential growth to antibiotic production. We have studied gene expression patterns during this switch, using specifically designed Affymetrix genechip and high-resolution time-series fermenter-grown samples. Surprisingly, we find that actually consists multiple finely orchestrated switching events. Strongly coherent clusters genes show drastic changes in already many hours before...
The intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of transcription factor Atoh1 required for both contribution secretory to cell pool a robust regenerative response. As confirmed lineage tracing, Atoh1+...
Many epithelial stem cell populations follow a pattern of stochastic divisions called 'neutral drift'. It is hypothesised that neutral competition between cells protects against the acquisition deleterious mutations. Here we use Porcupine inhibitor to reduce Wnt secretion at dose where intestinal homoeostasis maintained despite reduction Lgr5+ cells. Functionally, there marked acceleration in monoclonal conversion, so crypts become rapidly derived from single cell. Stem located further base...
Significance Colorectal cancer (CRC) is a heterogeneous disease, with significant variation in genotype and phenotype within each individual tumor. This intratumor heterogeneity emerges during tumor development due to clonal evolution part can explain therapy resistance CRC. However, detailed understanding of the spatiotemporal tumors underlying remains absent. Here, we use lineage-tracing experiments human CRC cells transplanted into immunocompromised mice, combination computational...
Bacteria in the genus Streptomyces are soil-dwelling oligotrophs and important producers of secondary metabolites. Previously, we showed that global messenger RNA expression was subject to a series metabolic regulatory switches during lifetime fermentor batch culture coelicolor M145. Here analyze proteome from eight time points same and, because phosphate availability is an regulator metabolite production, compare this similar course S. mutant, INB201 (ΔphoP), defective control utilization....
The proliferative and functional heterogeneity among seemingly uniform cells is a universal phenomenon. Identifying the underlying factors requires single-cell analysis of function proliferation. Here we show that pancreatic beta-cells in zebrafish exhibit different growth-promoting properties, which part reflect differences time elapsed since birth cells. Calcium imaging shows embryonic islet become during early development. At later stages, younger join following differentiation from...
Cancer driver mutations are defined by their high prevalence in cancers and presumed rarity normal tissues. However, recent studies show that positive selection epithelia can increase the of some cancer drivers. To determine true cancer-driving potential, it is essential to evaluate how frequent these tissues what phenotypes. Here, we explore bioavailability somatic variants quantifying age-related mutational burdens human colonic epithelium using immunodetection FFPE samples (N = 181...
Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of main embryonic arteries. The onset circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when affects emergence. Here we show in Ncx1−/− mouse embryos devoid lineage develops until phenotypic pro-HSC stage. However, these reside an abnormal microenvironment, fail to activate hematopoietic program downstream Runx1, are...
Pomelo II (http://pomelo2.bioinfo.cnio.es) is an open-source, web-based, freely available tool for the analysis of gene (and protein) expression and tissue array data. implements: permutation-based tests class comparisons (t-test, ANOVA) regression; survival using Cox model; contingency table with Fisher's exact test; linear models (of which t-test ANOVA are especial cases) that allow additional covariates complex experimental designs use empirical Bayes moderated statistics....
Abstract Motivation: Gene expression measurements are the most common data source for reverse engineering gene interaction networks. When dealing with destructive sampling in time course experiments, it is to average any available each point and treat this as actual series fitting network, neglecting variability contained repeated measurements. Proceeding such a way can affect retrieved network topology. Results: We propose fully Bayesian method based on The observations treated surrogate of...
We propose a semiparametric Bayesian model, based on penalized splines, for the recovery of time-invariant topology causal interaction network from longitudinal data. Our motivation is inference gene regulatory networks low-resolution microarray time series, where existence nonlinear interactions well known. Parenthood relations are mapped by augmenting model with kinship indicators and providing these either an overall or gene-wise hierarchical structure. Appropriate specification prior...
Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved studying single TF binding events in isolation. Chromosomal translocations lysine methyltransferase 2A (KMT2A) produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), causing poor prognosis acute lymphoblastic...
The tissue dynamics that govern maintenance and regeneration of the pancreas remain largely unknown. In particular, presence nature a cellular hierarchy remains topic debate. Previous lineage tracing strategies in relied on specific marker genes for clonal labeling, which left other populations untested failed to account potential widespread phenotypical plasticity. Here we employed system depends replication-induced marks. We found that, homeostasis, steady acinar replacement events...
Asterias (http://www.asterias.info) is an open-source, web-based, suite for the analysis of gene expression and aCGH data. implements validated statistical methods, most applications use parallel computing, which permits taking advantage multicore CPUs computing clusters. Access to, further of, additional biological information annotations (PubMed references, Gene Ontology terms, KEGG Reactome pathways) are available either individual genes (from clickable links in tables figures) or sets...
The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early development. Prior work has shown murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where cellular hierarchy GATA1s exerts its effects to this state. Here, through detailed...
Colorectal cancer (CRC) is thought to arise when the cumulative mutational burden within colonic crypts exceeds a certain threshold that leads clonal expansion and ultimately neoplastic transformation. Therefore, quantification of fixation subsequent somatic mutations in normal epithelium key understanding colorectal initiation. The aim present study was determine how advantaged expansions can be accommodated human colon.Immunohistochemistry used visualize loss driver KDM6A formalin-fixed...