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

Jessy Cartier, Chinthika Piyasena, Sarah Sparrow, James Boardman, Amanda Drake

Research output: Contribution to journalArticlepeer-review

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 if 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 1year. These developmental changes also occurred in rat brains in vivo, alongside changes in global DNA hydroxymethylation and
expression of the Ten-eleven-translocation enzyme Tet1, and were reproducible in ex vivo rat cortical slices. Based on the observation that neonatal glucose homeostasis can modify neurodevelopmatal 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.
Original languageEnglish
JournalEuropean Journal of Neuroscience
Early online date8 Feb 2018
DOIs
Publication statusE-pub ahead of print - 8 Feb 2018

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