A5061361435- CRISPR and Genetic Engineering
- Pancreatic function and diabetes
- Diabetes Management and Research
- Cancer-related Molecular Pathways
- Diabetes and associated disorders
- Cancer Research and Treatments
- Pluripotent Stem Cells Research
- Pancreatic and Hepatic Oncology Research
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Gestational Diabetes Research and Management
- RNA modifications and cancer
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Molecular Biology Techniques and Applications
Duke Medical Center
2023-2025
National Human Genome Research Institute
2023-2024
National Institutes of Health
2023-2024
University of Canterbury
2017
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes T2D risk. We examined impacts each on β differentiation, functions, and survival. generated gene expression chromatin accessibility profiles cells derived from line. Analyses T2D-association signals overlapping HNF4A-dependent ATAC peaks a likely causal variant at FAIM2...
We developed an efficient CRISPR prime editing protocol and generated isogenic-induced pluripotent stem cell (iPSC) lines carrying heterozygous or homozygous alleles for putatively causal single nucleotide variants at six type 2 diabetes loci (ABCC8, MTNR1B, TCF7L2, HNF4A, CAMK1D, GCK). Our two-step sequence-based approach to first identify transfected pools with the highest fraction of edited cells significantly reduced downstream efforts isolate clones cells. found that can make targeted...
The tumor suppressor p53 (Trp53), also known as p53, is the most commonly mutated gene in cancer. Canonical DNA damage response pathways are well characterized and classically thought to underlie suppressive effect of p53. Challenging this dogma, mouse models have revealed that p53-driven apoptosis cell cycle arrest dispensable for suppression. Here, we investigated inverse context a mutation predicted drive expression canonical targets but detected human We established novel model with...
Tp53 is the most commonly mutated gene in cancer. Canonical DNA damage response pathways are well characterized and classically thought to underlie tumor suppressive effect of Tp53. Challenging this dogma, mouse models have revealed that p53 driven apoptosis cell cycle arrest dispensable for suppression. Here, we investigated inverse context a mutation predicted drive expression canonical targets, but detected human
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, survival. performed RNA-seq ATAC-seq on hESC-β cells from each line. Analyses GWAS signals overlapping HNF4A-dependent ATAC peaks a specific SNP as likely...
Abstract Aims/hypothesis Disruption of pancreatic islet function and glucose homeostasis can lead to the development sustained hyperglycaemia, beta cell glucotoxicity subsequently type 2 diabetes. In this study, we explored effects in vitro hyperglycaemic conditions on human gene expression across 24 h six types: alpha; beta; gamma; delta; ductal; acinar. We hypothesised that genes associated with may be relevant onset progression Methods exposed islets from two donors low (2.8 mmol/l) high...