Biology subjects

Waite, E.

Publications and source records attributed to Waite, E..

4 recordsLinked to original sources

bioRxiv2026

The ortholog of the Human T2D Risk Gene STEAP2 is Required for Glucose Stimulated Insulin Secretion in Mice

Type 2 diabetes is a complex metabolic disease with a strong genetic component, yet this genetic risk is driven by common variants in up to 600 loci with small effect sizes. Variants in the STEAP2 locus, encoding Six-transmembrane epithelial antigen of the prostate-2, are highly associated with altered glycemic traits and type 2 diabetes risk. To elucidate its function in pancreatic beta-cells, we utilized Crisp-Cas9 assisted homologous recombination to derive a conditional null allele for Steap2 (Steap2fl/fl) in mice and crossed this to the rat insulin promoter (Rip)-Cre transgene. Ablation of Steap2 induced glucose intolerance, blunted glucose-stimulated Ca2+ mobilization and stunted first phase glucose-simulated insulin secretion. In contrast, the incretin effect and second phase insulin secretion were not affected. Islet respirometry and transmission electron microscopy (TEM) identified disrupted cristate morphology and impaired glucose-stimulated oxygen consumption as causally responsible for the observed, impaired triggering pathway of insulin secretion. These findings suggest that at least part of the genetic risk for T2D conferred by Steap2 variants is likely due to its function in maintaining optimal mitochondrial respiration in pancreatic beta-cells.

genetics↗

bioRxiv2023

G6PC2 controls glucagon secretion by defining the setpoint for glucose in pancreatic α-cells

Impaired glucose suppression of glucagon secretion (GSGS) is a hallmark of type 2 diabetes. A critical role for -cell intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the G6PC2 locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c levels. Here, we find that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in {beta}- but also in -cells, and document allele-specific G6PC2 expression of linked variants in human - cells. Using -cell specific gene ablation of G6pc2 in mice, we show that this gene plays a critical role in controlling glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology; findings we confirmed in primary human -cells. Collectively, our data demonstrate that G6PC2 impacts glycemic control via its action in -cells and suggest that G6PC2 inhibitors could help control blood glucose through a novel, bi-hormonal mechanism.

genetics↗

bioRxiv2020

Binding partners regulate unfolding of myosin VI to activate the molecular motor

Myosin VI is the only minus-end actin motor and is coupled to various cellular processes ranging from endocytosis to transcription. This multi-potent nature is achieved through alternative isoform splicing and interactions with a network of binding partners. There is a complex interplay between isoforms and binding partners to regulate myosin VI. Here, we have compared the regulation of two myosin VI splice isoforms by two different binding partners. By combining biochemical and single-molecule approaches, we propose that myosin VI regulation follows a generic mechanism, independently of the spliced isoform and the binding partner involved. We describe how myosin VI adopts an autoinhibited backfolded state which is released by binding partners. This unfolding activates the motor, enhances actin binding and can subsequently trigger dimerization. We have further expanded our study by using single molecule imaging to investigate the impact of binding partners upon myosin VI molecular organisation and dynamics.

biophysics↗

bioRxiv2020

Nuclear myosin VI regulates the spatial organization of mammalian transcription initiation.

During transcription, RNA Polymerase II (RNAPII) is spatially organised within the nucleus into clusters that correlate with transcription activity. While this is a hallmark of genome regulation in mammalian cells, the mechanisms concerning the assembly, organisation and stability which underpin the function these transcription factories remain unknown. Here, we have used combination of single molecule imaging and genomic approaches to explore the role of nuclear myosin VI in the nanoscale organisation of RNAPII. We reveal that myosin VI acts as the molecular anchor that holds RNAPII into transcription factories. Perturbation of myosin VI leads to the disruption of RNAPII localisation, changes in chromatin organisation and subsequently a decrease in gene expression. Overall, we uncover the fundamental role of myosin VI in the spatial regulation of gene expression during the rapid response to changes in the cellular environment.

cell biology↗