Biology subjects

Millership, S. J.

Publications and source records attributed to Millership, S. J..

2 recordsLinked to original sources

bioRxiv2020

Epigenetic change induced by in utero dietary challenge provokes phenotypic variability across multiple generations of mice

Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, histone H3K9me3, H3K27me3, H4K16ac and DNA methylation1-3. In higher vertebrates, epidemiological and experimental evidence supports similar trans-generational effects4,5 although the mechanisms that underpin these are incompletely understood6-9. We generated a luciferase reporter knock-in mouse for the imprinted Dlk1 locus, to visualise and track epigenetic fidelity across generations. We showed that exposure to high-fat diet (HFD) in pregnancy provokes sustained re-expression of the normally silent maternal Dlk1 allele in offspring, coincident with increased DNA methylation at the Dlk1 sDMR. Interestingly, maternal Dlk1 mis-expression was also evident in the next generation (F2), exclusively in animals derived from F1-exposed females. Oocytes from these females showed altered microRNA and gene expression, without any major changes in underlying DNA methylation, and correctly imprinted Dlk1 expression resumed in subsequent generations (F3 onwards). Our results reveal how canonical and non-canonical imprinting mechanisms enable the foetal epigenome to adapt to in utero challenge to modulate the properties of two successive generations of offspring.

developmental 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↗