Epigenetic programming by maternal behavior

2004

Early life experiences shape an individual's physical and mental health across the lifespan. Not surprisingly, an upbringing that is associated with adversity can produce detrimental effects on health. A central theme that arises from studies in human and nonhuman species is that the effects of adversity are mediated by the interactions between a mother and her young. In this review we describe some of the long-term effects of maternal care on the offspring and we focus on the impact of naturally occurring variations in the behavior of female rats. Of particular interest are mothers that engage in high or low amounts of licking/grooming (LG) and arched-back nursing (ABN) of their pups, but do so within the normal range for this species. Such variations in LG-ABN can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, and cognitive and emotional development by directly affecting the underlying neural mechanisms. At the heart of these mechanisms is gene expression. By studying the hippocampal glucocorticoid receptor gene, we have identified that maternal care regulates its expression by changing two processes: the acetylation of histones H3-K9, and the methylation of the NGFI-A consensus sequence on the exon 1 7 promoter. Sustained "maternal effects" appear elsewhere in biology, including plants, insects, and lizards, and may have evolved to program advantages in the environments that the offspring will likely face as adults. Given the importance of early life and parent-child interactions to later behavior, prevention and intervention programs should target this critical phase of development.

Pediatrics, 2018

OBJECTIVES: We sought to determine if variations in maternal care alter DNA methylation in term, healthy, 5-month-old infants. This work was based on landmark studies in animal models demonstrating that nurturing care by dams would alter their newborns’ stress responses through epigenetic mechanisms. We used breastfeeding as a proxy for animal maternal behavior. We hypothesized alterations in DNA methylation of the glucocorticoid receptor gene and less hypothalamic stress response in infants of mothers who breastfed their infants versus infants of mothers who did not breastfeed. METHODS: A cohort study of term, healthy infants and their mothers who did (n = 21) or did not (n = 21) breastfeed for the first 5 months was used in this analysis. Cortisol stress reactivity was measured in infant saliva by using a mother-infant interaction procedure and DNA methylation of an important regulatory region of the glucocorticoid receptor gene. Changes in DNA methylation of this gene in humans w...

Background: Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care.

Frontiers in Neuroendocrinology, 2005

Increased levels of pup licking/grooming and arched-back nursing by rat mothers over the first week of life alter the epigenome at a glucocorticoid receptor gene promoter in the hippocampus of the offspring. Differences in the DNA methylation pattern between the offspring of High and Low licking/grooming-arched-back mothers emerge over the first week of life, are reversed with cross-fostering, persist into adulthood and are associated with altered histone acetylation and transcription factor (NGFI-A) binding to the glucocorticoid receptor promoter. Central infusion of the adult offspring with the histone deacetylase inhibitor trichostatin A removes the previously defined epigenomic group differences in histone acetylation, DNA methylation, NGFI-A binding, glucocorticoid receptor expression, and hypothalamic-pituitary-adrenal responses to stress, thus suggesting a causal relation between the epigenomic state, glucocorticoid receptor expression and the effects of maternal care on stress responses in the offspring. These findings demonstrate that an epigenomic state of a gene can be established through a behavioral mode of programming and that in spite of the inherent stability of this epigenomic mark, it is dynamic and potentially reversible.

The Journal of Neuroscience, 2005

Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 17glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acidl-methionine, a precursor toS-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 17promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible i...

Proceedings of the National Academy of Sciences, 2006

Early-life experience has long-term consequences on behavior and stress responsivity of the adult. We previously proposed that early-life experience results in stable epigenetic programming of glucocorticoid receptor gene expression in the hippocampus. The aim of this study was to examine the global effect of early-life experience on the hippocampal transcriptome and the development of stress-mediated behaviors in the offspring and whether such effects were reversible in adulthood. Adult offspring were centrally infused with saline vehicle, the histone deacetylase inhibitor trichostatin A (TSA), or the essential amino acid L-methionine. The animals were assessed in an unfamiliar open-field arena, and the hippocampal transcriptome of each animal was evaluated by microarray analysis. Here we report that TSA and methionine treatment reversed the effect of maternal care on open-field behavior. We identified >900 genes stably regulated by maternal care. A fraction of these differences in gene expression is reversible by either the histone deacetylase inhibitor TSA or the methyl donor L-methionine. These results suggest that early-life experience has a stable and broad effect on the hippocampal transcriptome and anxiety-mediated behavior, which is potentially reversible in adulthood.

Erzincan Üniversitesi Fen Bilimleri Enstitüsü Dergisi

The aim of this study was to investigate the effects of prenatal stress (PS) on mRNA levels of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) in cerebral cortex and hippocampus of female rats. PS was induced in rats with dexamethasone (Dex). From gestation day 14 to 21, pregnant rats were injected daily with Dex (100 μg/kg) or saline. After birth, at 3 months of age, female rats were decapitated (n=5). The effects of Dex on epigenetic mechanisms were investigated by real-time PCR through mRNA levels of DNMT1, DNMT3a, DNMT3b, HDAC1 and HDAC2. Statistical significant differences were determined with one-way analysis of variance. Prenatal Dex exposure caused significant increases in DNMT3a, HDAC1 and HDAC2 mRNA levels in cortex and hippocampus. We further found that DNMT3b mRNA levels significantly increased in hippocampus but decreased in cortex of Dex group. No significant differences were found in DNMT1 mRNA levels. It was concluded that PS may trigger dysregulation...

Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCOR-TICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location , forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience. conservation | neuronal plasticity V ariation in early life experience is associated with differences in lifelong health and behavioral trajectories in animals as well as humans. For example, differences in maternal care in rats during the first week of life are associated with long-term effects on behavior and brain function that persist into adult-hood, including alterations in the stress response (1). In humans, similar effects are observed. For instance, childhood maltreat-ment associates with development of both externalizing and in-ternalizing personality traits and psychopathology in adulthood (2). The association in both rats and humans of stable developmental phenotypes with early life experience suggests that molecular mechanisms may serve as a memory of these early life experiences in both species. In fact, there is evidence that these long-term effects are, at least in part, mediated by epigenetic alterations in the brain. In particular, recent studies have found aberrant DNA methylation in the NR3C1 (GLUCOCORTICOID RECEPTOR) gene promoter of the hippocampi of both rats and humans associated with differential early life experience (3, 4). Exposure of infant rats to stressed caretakers displaying abusive behavior produced persisting changes in methylation of the BDNF gene promoter in the adult prefrontal cortex (5). Early life stress in mice caused sustained DNA hypomethylation of an important regulatory region of the AVP gene (6). Although explanations involving a single site are appealing, it is unlikely that the broad systemic response to early life experience would be associated with a few site-specific epigenetic changes. Indeed, we have previously shown that several hundred genes are differentially expressed in the hippocampi of adult rat offspring that received low compared with high maternal licking and grooming (LG) (7). Moreover, in the hippocampi of humans with documented childhood abuse, we have recently discovered methylation differences in the rRNA gene promoters that are scattered across the genome (8). Furthermore, recent evidence suggests that epigenetic regulation is not restricted to the few thousand bases around the transcription start sites of genes. Epigenetic changes associated with transcriptional changes can appear within the body of a gene (9) or even at high frequency across megabase-sized domains simultaneously deactivating dozens of neighboring genes (10, 11). These results led us to hypothesize that the epigenetic response to early life experience is not limited to a single gene promoter but that NR3C1, along with neighboring genes, might belong to a domain under coordinated control. To test this hypothesis, we recently investigated DNA methylation, H3K9 acetylation, and transcriptional profiles in a region encompassing 6.5 million base pairs centered at NR3C1 in the hippocampus of adult rat offspring of high and low LG (12). We confirmed our hypothesis by identifying hundreds of robust DNA methylation differences between the offspring of high and low LG that were scattered across this large region. Considering the parallel behavioral and epigenetic responses in humans and rats to early life environments described above, it is reasonable to assume that at least part of the broad epigenetic responses observed in rats to early life experiences may be evo-lutionarily conserved in humans. Therefore, in this study we investigated the extent of this conservation in humans by generating epigenetic profiles of the analogous region in humans, the 6.5 million base pair region centered at NR3C1 (heretofore referred as the NR3C1 locus). Such a cross-species investigation is further supported by the fact that there is an ∼35% sequence homology between the rat and human NR3C1 loci, and that 80% of the genes in the human region have orthologs in the rat region.

Journal of Neuroscience, 2010

Parenting and the early environment influence the risk for various psychopathologies. Studies in the rat suggest that variations in maternal care stably influence DNA methylation, gene expression, and neural function in the offspring. Maternal care affects neural development, including the GABAergic system, the function of which is linked to the pathophysiology of diseases including schizophrenia and depression. Postmortem studies of human schizophrenic brains have revealed decreased forebrain expression of glutamic acid decarboxylase 1 (GAD1) accompanied by increased methylation of a GAD1 promoter. We examined whether maternal care affects GAD1 promoter methylation in the hippocampus of adult male offspring of high and low pup licking/grooming (high-LG and low-LG) mothers. Compared with the offspring of low-LG mothers, those reared by high-LG dams showed enhanced hippocampal GAD1 mRNA expression, decreased cytosine methylation, and increased histone 3-lysine 9 acetylation (H3K9ac) of the GAD1 promoter. DNA methyltransferase 1 expression was significantly higher in the offspring of low-compared with high-LG mothers. Pup LG increases hippocampal serotonin (5-HT) and nerve growth factor-inducible factor A (NGFI-A) expression. Chromatin immunoprecipitation assays revealed enhanced NGFI-A association with and H3K9ac of the GAD1 promoter in the hippocampus of high-LG pups after a nursing bout. Treatment of hippocampal neuronal cultures with either 5-HT or an NGFI-A expression plasmid significantly increased GAD1 mRNA levels. The effect of 5-HT was blocked by a short interfering RNA targeting NGFI-A. These results suggest that maternal care influences the development of the GABA system by altering GAD1 promoter methylation levels through the maternally induced activation of NGFI-A and its association with the GAD1 promoter.

Endocrinology, 2014

In many species, including mice, maternal responsiveness is experience-dependent and permanent, lasting for long periods (months to years). We have shown that after brief exposures to pups, virgin female mice continue to respond maternally toward pups for at least one month. Administration of a histone deacetylase inhibitor (HDACi) reduces the amount of maternal experience required to affect maternal behavior and gene expression. In this set of studies, we examined the epigenetic mechanisms that underlie these motivated behaviors. We assessed whether the effects of HDACi persisted 1 month after the initial experience (in the absence of continued pup experience or HDACi treatment) and whether the maintenance of maternal memory was associated with stable changes in gene expression. Using chromatin immunoprecipitation, we examined whether Esr2 and Oxt gene expression might be mediated by recruitment of the histone acetyltransferase cAMP response element binding protein (CBP) to their p...