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Early childhood adversity may have long-term effects on gene expression

by CIFAR Dec 12 / 16

Difficult childhood experiences can often lead to poor physical and mental health later on in life.

The signature of DNA methylation left behind in adolescent brains suggests that early childhood adversity may make changes to neurological and development genes that can persist for years.

This study explores the effects of early experiences on gene expression. It compares the epigenomes of immune cells in the peripheral blood of two groups of adolescents: one adopted as young children from conditions of significant adversity and the other raised by their own parents from birth in a secure and supportive environment.

BACKGROUND

A large body of research has shown that adverse childhood experiences often lead to poor physical and mental health in the long term. Many processes may account for these impacts, including learned behaviour patterns that influence children’s perception of their experiences, and effects on brain development that limit learning capacity, or that develop defensive systems that limit engagement with ther environment.

To explain these findings, previous studies have examined stress hormones, brain function, brain structure and molecular processes. More recent work has explored how early experiences influence later outcomes by sculpting the epigenome.

Epigenetics refers to modifications of the genome that affect DNA accessibility and potentially alter gene expression, but do not change the base-pair sequence. One type of modification is DNA methylation, which adds a methyl group to the cytosine in a C-G dinucleotide (CpG) of DNA. CpGs, which are unevenly distributed in the genome, tend to be clustered in regions called “CpG islands”. Many genes have a promoter-associated CpG island, and DNA methylation of these islands is often linked to gene expression levels. DNA methylation is also tightly linked to cell differentiation and identity; cellular heterogeneity within a tissue is one of the key predictors of epigenetic variability.

Recent research has suggested that DNA methylation acts as a principal mechanism by which early-life experiences affect neurobehavioral development in mammals. In humans, childhood experiences such as low socioeconomic status and maltreatment have been associated with altered DNA methylation and gene expression later in life.

One study involving children in a Russian orphanage compared their genome-wide DNA methylation patterns in peripheral whole blood with those of children brought up in poverty in their Russian birth families. It found increased DNA methylation across a number of CpG loci in the orphanage children, particularly those located in genes related to immune regulation and cellular signalling.

This study builds on this research to determine whether exposure to adverse conditions from conception through infancy leaves behind a signature of DNA methylation that remains up until middle adolescence — despite a vast improvement in children’s environments at around age two.

FINDINGS

The type of immune cells in circulation differed strikingly between the adopted and nonadopted groups. The white blood cells of the adopted adolescents exhibited fewer CD4þ and more CD8þ cells than the nonadopted youth and fewer B cells. This pattern suggests a reduced immune competence that may have some adaptive significance in the environment in which these children were conceived and raised prior to adoption. However, there were no significant differences in their physical health.

Thirty CpG sites were more methylated in the adopted group. After correcting for cell-type differences and restricting the analysis to variable CpG loci, the researchers identified 30 methylated sites on 19 genes in the group of adopted adolescents.

Because cellular composition changes with age, it is critical to take it into account in studies of DNA methylation.

The differences between the two groups in gene ontology (GO) terms were clustered in the neuronal and developmental areas. An exploratory functional analysis revealed a total of 223 enriched gene ontology terms in the adopted adolescents. Since many of the high-ranking methylated genes were multifunctional, they had many GO terms associated with them. The two main gene clusters were neuronal and developmental. These results are consistent with behavioral and health differences previously noted for children adopted from Eastern European orphanages. 

METHODOLOGY

The epigenome-wide association study compared the DNA methylation profiles of 83 Caucasian adolescents, with an average age of 15, at approximately 416,000 individual CpG loci from peripheral blood mononuclear cells (PBMCs).

Of these adolescents, 50 were Russian or Eastern European orphans who had spent their earliest years in orphanages and then were adopted, on average at 22 months, by Midwestern families in the United States; the remaining 33 were born and brought up in the Midwest by their birth families. Both sets of parents were well-educated (minimum of bachelor degree) and financially comfortable (annual income between $85,001 and$100,000). Thus, roughly 80 per cent of the teenagers’ lives were spent in similar circumstances. Parents and children completed questionnaires to probe physical and mental health and to assess stress in the previous years.

The researchers estimated the underlying white blood cell composition to control for it. After correcting for cell-type differences (in CD4T/CD8T cell ratios) and removing invariable CpG loci, they produced a list of 8,700 variable sites. From these, they identified the sites and genes that were methylated in the adopted children. They also used an exploratory functional analysis of GO terms and tested for significant enrichment. The GO terms were then clustered according to shared genes.

REFERENCE

Differential DNA methylation in peripheral blood mononuclear cells in adolescents exposed to significant early but not later childhood adversity. Elisa A. Esposito et al., Development and Psychopathology, 1-15 (2016).

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