Biology subjects

Ibberson, M.

Publications and source records attributed to Ibberson, M..

5 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

dsSwissKnife: An R package for federated data analysis

SummarydsSwissKnife is an R package that enables several powerful analyses to be performed on federated datasets. The package works alongside DataSHIELD and extends its functionality. We have developed and implemented dsSwissKnife in a large IMI project on type 2 diabetes, RHAPSODY, where data from 10 observational cohorts have been harmonised and federated in CDISC SDTM format and made available for biomarker discovery. Availability and implementationdsSwissKnife is freely available online at https://github.com/sib-swiss/dsSwissKnife. The package is distributed under the GNU General Public License version 3. Contactmark.ibberson@sib.swiss

bioinformatics↗

bioRxiv2020

MetaNetX/MNXref - unified namespace for metabolites and biochemical reactions in the context of metabolic models

MetaNetX/MNXref is a reconciliation of metabolites and biochemical reactions providing cross-links between major public biochemistry and Genome-Scale Metabolic Network (GSMN) databases. The new release brings several improvements with respect to the quality of the reconciliation, with particular attention dedicated to preserving the intrinsic properties of GSMN models. The MetaNetX website (https://www.metanetx.org/) provides access to the full database and online services. A major improvement is for mapping of user-provided GSMNs to MXNref, which now provides diagnostic messages about model content. In addition to the website and flat files, the resource can now be accessed through a SPARQL endpoint (https://rdf.metanetx.org).

systems biology↗

bioRxiv2020

Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

Variants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B. Here, we show that systemic inactivation of C2cd4b in mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. Female C2cd4b mice display unchanged body weight but abnormal glucose tolerance and defective in vivo, but not in vitro, insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, male C2cd4b null mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic {beta} cell function at larval stages in C2cd4ab null zebrafish. These studies suggest that C2cd4b may act centrally to influence sex-dependent circuits which control pancreatic {beta} cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in man.

genetics↗

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↗