Biology subjects

Schulte, A.

Publications and source records attributed to Schulte, A..

3 recordsLinked to original sources

bioRxiv2020

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories toward type 2 diabetes

Existing studies do not sufficiently describe the molecular changes of pancreatic islet beta cells leading to their deficient insulin secretion in type 2 diabetes (T2D). Here we address this deficiency with a comprehensive multi-omics analysis of metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum from normoglycemia to T2D. Islet pools isolated from surgical samples by laser-capture microdissection had remarkably heterogeneous transcriptomic and proteomic profiles in diabetics, but not in non-diabetic controls. Transcriptomics analysis of this unique cohort revealed islet genes already dysregulated in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive but disharmonic remodeling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or trans-differentiation stages in T2D. Further, integration of islet transcriptomics and pre-operative blood plasma lipidomics data enabled us to define the relative importance of gene co-expression modules and lipids positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.

bioinformatics↗

bioRxiv2020

Vibrio campbellii chitoporin: thermostability study and implications for the development of therapeutic agents against Vibrio infections

Vibrio campbellii (formerly Vibrio harveyi) is a bacterial pathogen that causes vibriosis, which devastates fisheries and aquaculture worldwide. V. campbellii expresses chitinolytic enzymes and chitin binding/transport proteins, which serve as excellent targets for antimicrobial agent development. We previously characterized VhChiP, a chitooligosaccharide-specific porin from the outer membrane of V. campbellii BAA-1116. This study employed far-UV circular dichroism and tryptophan fluorescence spectroscopy, together with single channel electrophysiology to demonstrate that the strong binding of chitoligosaccharides enhanced thermal stability of VhChiP. The alanine substitution of Trp136 at the center of the affinity sites caused a marked decrease in the binding affinity and decreased the thermal stability of VhChiP. Tryptophan fluorescence titrations over a range of temperatures showed greater free-energy changes on ligand binding ({Delta}G{degrees}binding) with increasing chain length of the chitooligosaccharides. Our findings suggest the possibility of designing stable channel-blockers, using sugar-based analogs that serve as antimicrobial agents, active against Vibrio infection.

biochemistry↗

bioRxiv2020

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

Genome-wide association studies have identified thousands of genetic variants associated with type 2 diabetes (T2D) risk. Using chromatin conformation capture we show that an enhancer cluster in the STARD10 T2D locus forms a defined 3D chromatin domain. A 4.1 Kb region within this region, carrying five disease-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of an associated enhancer, in human pancreatic beta cells impaired glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2, but not ARAP1, was reduced in cells harboring CRISPR deletions, and expression of STARD10 and FCHSD2 was associated with the possession of variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2 impaired regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence {beta} cell function.

cell biology↗