Alterations in glucose concentrations affect DNA methylation at Lrg1 in an ex vivo rat cortical slice model of preterm brain injury

Abstract

Preterm birth affects 5-18% of all babies and is associated with neurodevelopmental impairment and increased neuropsychiatric disease risk. Although preterm birth associates with differential DNA methylation at neurodevelopmental genes in buccal DNA, including leucine-rich alpha-2-glycoprotein 1 (LRG1), it is not known whether these differences also occur in the brain, or whether they persist. Thus, there is a need for animal models or in vitro systems in which to undertake longitudinal and mechanistic studies. We used a combination of in vivo rat studies and ex vivo experiments in rat cortical slices to explore their utility in modelling the human preterm brain. We identified temporal changes in DNA methylation at LRG1 in human buccal DNA over the first year of life and found persistent differences in LRG1 methylation between preterm and term infants at 1 year. These developmental changes also occurred in rat brains in vivo, alongside changes in global DNA hydroxymethylation and expression of the ten-eleven translocation (Tet1) enzyme, and were reproducible in ex vivo rat cortical slices. On the basis of the observation that neonatal glucose homeostasis can modify neurodevelopmental outcome, we studied whether glucose concentration affects Lrg1 methylation using cortical slices. Culture of slices in lower glucose concentration was associated with lower Lrg1 methylation, lower global 5hmC and Tet1 expression. Our results suggest that ex vivo organotypic cultures may be useful in the study of biological and environmental influences on the epigenome and that perturbations during early life including glucose concentration can affect methylation at specific genes implicated in neurodevelopment.

Neonatal hyperglycaemia is associated with worse neurodevelopmental outcomes in extremely preterm infants

“…Higher methylation of leucine-rich alpha-2-glycoprotein 1 (a protein associated with neurodevelopment), as well as upregulation of poly (ADP-ribose) polymerase-1 and NF-kB expression (associated with microglial activation) were associated with higher glucose concentrations. 27 28 In EPT infants, hyperglycaemia >8.3 mmol/L on the first day of life was associated with white matter reduction at term-equivalent age. 7 A meta-analysis concluded that neonatal hypoglycaemia was associated with visual-motor impairments, thus implying a possible effect of hyperglycaemia on motor development.…”

Research Progress on Leucine-Rich Alpha-2 Glycoprotein 1: A Review

“…LRG1 got more superior performance than interleukin-6 in the prediction for inflammatory diseases of the central nervous system (Chong et al, 2018). Cartier et al (2018) Hippocampal LRG1 overexpression contributed to fewer synaptic vesicles and junctions, which led to memory impairment with increased age (Akiba et al, 2017). Three protein expression LRG1, secretoglobin family 3A member 1, and peptidoglycan recognition protein one were mainly associated with inflammation and apoptosis and they regulated the regeneration of nerves (Zheng et al, 2019).…”

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

“…Considering the mother is the sole source of nutrition during this time, nutritional deficits could confound any findings in this model. Indeed, we have previously shown that extended periods of maternal separation in rats results in hypoglycaemia [32], which is independently associated with impaired neurodevelopment [33]. Further, traditional maternal separation models may not accurately recapitulate some of the common stressors associated with the NICU, including frequent handling and sleep deprivation.…”