Nicola L. Beer
A5036749296- Pancreatic function and diabetes
- Genetic Associations and Epidemiology
- Metabolism, Diabetes, and Cancer
- Diabetes and associated disorders
- Diabetes Management and Research
- Genetics and Neurodevelopmental Disorders
- Bioinformatics and Genomic Networks
- Diabetes Treatment and Management
- Pluripotent Stem Cells Research
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Endoplasmic Reticulum Stress and Disease
- Liver Disease Diagnosis and Treatment
- Genetic Mapping and Diversity in Plants and Animals
- Nutrition, Genetics, and Disease
- Cardiovascular Disease and Adiposity
- Adipokines, Inflammation, and Metabolic Diseases
- Analog and Mixed-Signal Circuit Design
- COVID-19 Clinical Research Studies
- PARP inhibition in cancer therapy
- Adipose Tissue and Metabolism
- Diet, Metabolism, and Disease
- MicroRNA in disease regulation
- Cancer-related gene regulation
University of Oxford
2012-2025
Centre for Human Genetics
2019-2025
Oxford Centre for Diabetes, Endocrinology and Metabolism
2012-2024
Novo Nordisk (United Kingdom)
2019-2021
Novo Nordisk (Denmark)
2021
Churchill Hospital
2011-2018
Broad Institute
2012-2014
Massachusetts Institute of Technology
2013
Genome-wide association studies have identified a number of signals for both Type 2 Diabetes and related quantitative traits. For the majority loci, transition from signal to mutational mechanism has been difficult establish. Glucokinase (GCK) regulates glucose storage disposal in liver where its activity is regulated by glucokinase regulatory protein (GKRP; gene name GCKR ). Fructose-6 fructose-1 phosphate (F6P F1P) enhance or reduce GKRP-mediated inhibition, respectively. A common variant...
To decipher the populations of cells present in human fetal pancreas and their lineage relationships, we developed strategies to isolate pancreatic progenitors, endocrine progenitors cells. Transcriptome analysis individual revealed a large degree conservation among vertebrates drivers gene expression changes occurring at different steps differentiation, although notably, sometimes, members same family are expressed. The transcriptome establishes resource identify novel genes pathways...
Translation of genetic association signals into molecular mechanisms for diabetes has been slow. The glucokinase regulatory protein (GKRP; gene symbol GCKR) P446L variant, associated with inverse modulation glucose- and lipid-related traits, shown to alter the kinetics (GCK) inhibition. As GCK inhibition is nuclear sequestration, we aimed determine whether this variant also alters direct interaction between GKRP their intracellular localisation.Fluorescently tagged rat human wild-type (WT)-...
Several distinct differentiation protocols for deriving pancreatic progenitors (PPs) from human pluripotent stem cells have been described, but it remains to be shown how similar the PPs are across and well they resemble their in vivo counterparts. Here, we evaluated three protocols, performed RNA assay transposase-accessible chromatin using sequencing on isolated derived with these, compared them fetal pancreas populations. This enabled us define a shared transcriptional epigenomic...
Abstract To enable robust expression of transgenes in stem cells, recombinase-mediated cassette exchange at safe harbor loci is frequently adopted. The choice recombinase enzyme a critical parameter to ensure maximum efficiency and accuracy the integration event. We have explored serine family site-specific integrases directly compared PhiC31, W-beta, Bxb1 integrase for targeted transgene Gt(ROSA)26Sor locus mouse embryonic cells. All 3 were found be suitable efficient engineering long-term...
Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology provide potential for directed gene- pathway-based prevention treatment. Common nonsynonymous in GCKR gene are associated with alterations metabolic traits, most notably serum triglyceride levels. encodes glucokinase regulatory protein (GKRP), predominantly nuclear inhibits hepatic (GCK) plays critical role glucose...
To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing 2,657 European individuals exome 12,940 multiple ancestries. Over 27M SNPs, indels, structural variants were identified, including 99% low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding in sequenced 99.7% coding whole-exome individuals. Each variant was tested for association with T2D individuals, and, increase power, most...
Inducible pluripotent stem cell–derived human β-like cells (BLCs) hold promise for both therapy and disease modeling, but their generation remains challenging functional analyses beyond transcriptomic morphological assessments remain limited. Here, we validate an approach using multicellular single-cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted more differentiated BLCs. The multi-electrode arrays (MEAs) measuring the...
Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes the young (GCK-MODY). Over 600 GCK have been reported which ∼65% are missense. In many cases co-segregation has not established and despite importance functional studies in ascribing pathogenicity for missense variants these only performed <10% mutations. The aim this study was to determine minimum prevalence GCK-MODY amongst diabetic subjects Slovakia by sequencing 100 Slovakian probands with phenotype...
Maturity onset diabetes of the young (MODY) is a hereditary form mellitus presenting at childhood or adolescence, which eventually leads to pancreatic β-cells dysfunction. The underlying genetic basis MODY disorders haploinsufficiency, where loss-of-function mutations in single allele cause diabetic phenotype heterozygous patients. MODY1 type disorder resulting from mutation transcription factor hepatocyte nuclear 4 alpha (HNF4α). In order establish human based model study MODY1, we...
Recent studies have reported significant advances in the differentiation of human pluripotent stem cells to clinically relevant cell types such as insulin producing beta-like and motor neurons. However, many current protocols lead heterogeneous cultures containing other than targeted fate. Genetically modified reporting expression specific genes are great value for protocol optimization purification populations from cultures. Here we present generation induced (iPSC) lines with a GFP...
Directed differentiation of stem cells offers a scalable solution to the need for human cell models recapitulating islet biology and T2D pathogenesis. We profiled mRNA expression at 6 stages an induced pluripotent (iPSC) model endocrine pancreas development from 2 donors, characterized distinct transcriptomic profiles associated with each stage. Established regulators endodermal lineage commitment, such as SOX17 (log2 fold change [FC] compared iPSCs = 14.2, p-value 4.9 × 10−5) pancreatic...
Type 2 diabetes is a global problem, and current ineffective therapeutic strategies pave the way for novel treatments like small molecular activators targeting glucokinase (GCK). GCK activity fundamental to beta cell hepatocyte glucose metabolism, heterozygous activating inactivating mutations cause hyperinsulinemic hypoglycemia (HH) maturity onset of young (MODY) respectively. Over 600 naturally occurring have been reported, whereas only 13 are documented date. We report two HH (V389L...
Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of correlated these with protein expression phenotype.9 clinical diagnosis WFS were studied quantitative PCR for markers endoplasmic reticulum (ER) stress immunoblotting fibroblast extracts expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded response (UPR)...
Liver disease is a major cause of premature death. Oxidative stress in the liver represents key driver. Compounds, such as dimethyl fumarate (DMF), can activate antioxidant response and are used clinically to treat disease. In this study, we tested protective properties DMF before or after paracetamol exposure. Following administration, Nrf2 nuclear translocation was tracked at single-cell level target gene transactivation confirmed. Next, were examined following Transcriptomic biochemical...
Type 2 Diabetes (T2D) constitutes a global health burden. Efforts to uncover predisposing genetic variation have been considerable, yet detailed knowledge of the underlying pathogenesis remains poor. Here, we constructed T2D phenotypic-linkage network (T2D-PLN), by integrating diverse gene functional information that highlight genes, which when disrupted in mice, elicit similar T2D-relevant phenotypes. Sensitising phenotypes enabled significant convergence be detected between genes...