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Preterm Birth is Associated with Alterations in the Methylome at Sites that Influence Neural Development

Presented at the Neonatal Society 2015 Spring Meeting.

Sparrow SA1, Manning J2, Piyasena C3, Pataky R1, Moore E1, Drake AJ3, Boardman JP1,4

1 MRC Centre for Reproductive Health, University of Edinburgh
2 Centre for Regenerative Medicine, University of Edinburgh
3 University/BHF Centre for Cardiovascular Sciences, University of Edinburgh
4 Centre for Clinical Brain Sciences, University of Edinburgh

Background: Early exposure to the extra-uterine environment is closely associated with altered brain development and long term neurodevelopmental impairment. DNA methylation, involving the addition of a methyl group to cytosine nucleotides, influences gene expression and is fundamental to normal neural development. DNA methylation is dynamic and can be influenced by stressful early life environmental exposures. We test the hypothesis that preterm birth affects the methylome, leading to differences between preterm infants at term equivalent age and term controls.

Methods: Subjects included 36 preterm infants (mean postmenstrual age [PMA] at birth 28+3 weeks, range 23+2 to 32+5) at term equivalent age (mean 39+5 weeks’ PMA, range 38+0 to 42+4) and 36 term controls (mean 41+2 weeks’ PMA, range 38+3 to 47+1), matched for sex. Ethical approval and informed parental consent were obtained. DNA was extracted from buccal cells. DNA methylation was measured at over 485,000 sites throughout the methylome using Illumina HM450 BeadChip array. Differential Methylation was assessed using RnBeads v 0.99.13.

Results: 18 protein coding genes and 33 protein coding associated promoters showed significantly different methylation between preterm and term infants (FDR-corrected combined p value <= 0.05). Genes of interest with regards to CNS development and signalling included:

Conclusion: Preterm birth is associated with alterations in the methylome at sites that influence neural function. DNA methylation may provide a molecular link between the stress of preterm birth and accompanying alterations in brain development.

Corresponding author: sarahannemitchell@hotmail.co.uk

References
1. Murphy S et al PloS ONE 2012
2. Klengel et al. Nature Neuroscience 2013
3. Khulan B et al. Translational Psychiatry 2014

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