Developmental dynamics of the epigenome: A longitudinal study of three toddlers.

Epigenetic regulation plays an important role in development, at the embryonic stages and later during the lifespan. Some epigenetic marks are highly conserved throughout the lifespan whereas others are closely associated with specific age periods and/or particular environmental factors. Little is known about the dynamics of epigenetic regulation during childhood, especially during the period of rapid early development. Our study was aimed to determine whether the developmental program at the early stages of human development is accompanied by significant changes in the systems of genome regulation, specifically, by genome-wide changes in DNA methylation. Using a sequencing approach (MBD-seq) we investigated genome-wide DNA methylation patterns in the T-lymphocytes of three healthy toddlers at two timepoints within the second year of life. Pairwise comparison of the methylation patterns across the individuals and time points was conducted to determine common longitudinal changes in the DNA methylation patterns. Despite relatively high interindividual variability in their epigenetic profiles and the dynamics of these profiles during the second year of life, all children showed consistent changes in the DNA methylation patterns of genes involved in the control of the immune system and genes related to the development of the CNS. Thereby, we provide evidence that early development might be accompanied by epigenetic changes in specific functional groups of genes; many such epigenetic changes appear to be related to the rapid development of the CNS.

Epigenetic Patterns Modulate the Connection Between Developmental Dynamics of Parenting and Offspring Psychosocial Adjustment.

This study attempted to establish and quantify the connections between parenting, offspring psychosocial adjustment, and the epigenome. The participants, 35 African American young adults (19 females and 16 males; age = 17-29.5 years), represented a subsample of a 3-wave longitudinal 15-year study on the developmental trajectories of low-income urban mother-offspring dyads. Mothers were assessed on their perceptions of maternal stress at each wave. Offspring were assessed on their perceptions of maternal parenting at each wave and on their adaptive and maladaptive behavior at the last wave. Genome-wide DNA methylation in peripheral T lymphocytes at the third wave was assayed using Methyl Binding Domain(MBD) sequencing. Statistically significant associations were identified between the change in offspring's perception of parenting from middle childhood to adulthood and the DNA methylation in offspring's adult genomes. Specifically, the slope of perceived parental rejection across the 3 time points was related to an increase in methylation, or a potential downregulation, of 565 genes thought to be involved in the control of a broad spectrum of biological functions generally related to cellular signaling. A subset of these epigenetic marks, clustered in 23 genes, some of which participate in the development and functioning of the CNS, were in turn associated with psychosocial adjustment as captured by interpersonal relationships and emotional self-evaluation. This appears to be one of the first investigations of the modulating role of the methylome in associations between developmental dynamics of parenting throughout the formative years of child and adolescent development and psychosocial adjustment in adulthood.

Childhood adversity and DNA methylation of genes involved in the hypothalamus-pituitary-adrenal axis and immune system: whole-genome and candidate-gene associations.

In recent years, translational research involving humans and animals has uncovered biological and physiological pathways that explain associations between early adverse circumstances and long-term mental and physical health outcomes. In this article, we summarize the human and animal literature demonstrating that epigenetic alterations in key biological systems, the hypothalamus-pituitary-adrenal axis and immune system, may underlie such disparities. We review evidence suggesting that changes in DNA methylation profiles of the genome may be responsible for the alterations in hypothalamus-pituitary-adrenal axis and immune system trajectories. Using some preliminary data, we demonstrate how explorations of genome-wide and candidate-gene DNA methylation profiles may inform hypotheses and guide future research efforts in these areas. We conclude our article by discussing the many important future directions, merging perspectives from developmental psychology, molecular genetics, neuroendocrinology, and immunology, that are essential for furthering our understanding of how early adverse circumstances may shape developmental trajectories, particularly in the areas of stress reactivity and physical or mental health.

Wnt pathway anomalies in developing amygdalae of Turner syndrome-like mice.

Certain neurobehavioral deficiencies associated with Turner Syndrome have been attributed to brain volumetric abnormalities, particularly of the amygdala. Haplo-insufficiency of a non-dosage compensated gene or genes on the X chromosome has been hypothesized to be the cause of the neuroanatomical defect. We examined gene expression levels of 6,628 genes in developing amygdalae of late-stage embryos of a mouse model for Turner Syndrome. In total, 161 genes show significant differences in expression level between TS and normal female amygdala. In silico pathway analysis of both X-linked and autosomal mis-regulated genes suggests that modulation of Wnt signaling is a critical factor in the normal growth and development of the amygdala.

Identification of a cluster of X-linked imprinted genes in mice.

Complete or partial monosomy with respect to the X chromosome is the genetic basis of Turner syndrome in human females. Individuals with Turner syndrome have a spectrum of anatomical, physiological and behavioral phenotypes with expressivity dependent on the extent of monosomy and the parental origin of the single X. Parent-of-origin influences on social cognition in Turner syndrome might be due to the presence of imprinted genes on the X. Imprinting of X-linked genes has also been implicated in the male prevalence of autistic spectrum disorders, in male sexual orientation and in the developmental delay of XO mouse embryos. The only molecular evidence for X-chromosome imprinting, however, concerns X-chromosome inactivation in specific circumstances and does not account for these phenotypes. Using a mouse model for Turner syndrome, we searched for locus-specific imprinting of X-linked genes in developing brain. We identified a cluster of X-linked genes containing at least three genes that show transcriptional repression of paternal alleles. Imprinting of these three genes, Xlr3b, Xlr4b and Xlr4c, is independent of X-chromosome inactivation and has a dynamic and complex pattern of tissue and stage specificity.