AUTHOR=Masemola Matshane L. , Merwe Lize van der , Lombard Zané , Viljoen Denis , Ramsay Michèle 

TITLE=Reduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero: a South African Fetal Alcohol Syndrome cohort study

JOURNAL=Frontiers in Genetics

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2015.00085

DOI=10.3389/fgene.2015.00085

ISSN=1664-8021

ABSTRACT=<p>Fetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from alcohol exposure during fetal development. It is a considerable public health problem worldwide and is characterized by central nervous system abnormalities, dysmorphic facial features, and growth retardation. Imprinted genes are known to play an important role in growth and development and therefore four imprinting control regions (ICRs), <italic>H19 ICR</italic>, <italic>IG-DMR</italic>, <italic>KvDMR1</italic> and <italic>PEG3 DMR</italic> were examined. It is proposed that DNA methylation changes may contribute to developmental abnormalities seen in FAS and which persist into adulthood. The participants included FAS children and controls from the Western and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive a quantitative estimate of methylation at selected CpG dinucleotides: <italic>H19 ICR</italic> (six CpG sites; 50 controls and 73 cases); <italic>KvDMR1</italic> (7, 55, and 86); <italic>IG-DMR</italic> (10, 56, and 84); and <italic>PEG3 DMR</italic> (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal development. In this study we report on epigenetic effects observed in blood which may not directly reflect tissue-specific alterations in the developing brain. After adjusting for age and sex (known confounders for DNA methylation), there was a significant difference at <italic>KvDMR1</italic> and <italic>PEG3 DMR</italic>, but not the <italic>H19 ICR</italic>, with only a small effect (0.84% lower in cases; <italic>p</italic> = 0.035) at <italic>IG-DMR</italic>. The two maternally imprinted loci, <italic>KvDMR1</italic> and <italic>PEG3 DMR</italic>, showed lower average locus-wide methylation in the FAS cases (1.49%; <italic>p</italic> &lt; 0.001 and 7.09%; <italic>p</italic> &lt; 0.001, respectively). The largest effect was at the <italic>PEG3 DMR</italic> though the functional impact is uncertain. This study supports the role of epigenetic modulation as a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of imprinted loci in a locus-specific manner.</p>