The secret language of destiny: stress imprinting and transgenerational origins of disease

Zucchi, Fabíola Cristina Ribeiro; Yao, Youli; Metz, Gerlinde A. S.

doi:10.3389/fgene.2012.00096

Cited by 38 publications

(24 citation statements)

References 167 publications

(234 reference statements)

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“…Imprinting , which is underlies parent of origin inheritance, is based on the differential DNA methylation of genes present on paternal or maternal chromosomes. For example, transmission of a particular deletion on chromosome 15 (q 11–13) from the mother produces Angelman syndrome, while transmission of a similar deletion from the father produces Prader-Willi syndrome, a much different phenotype (31). Genes such as IGF2 and IGF2R are imprinted (32), and are also known to be epigenetically modified under certain conditions of prenatal adversity.…”

Section: Dna Methylationmentioning

confidence: 99%

DNA methylation, early life environment, and health outcomes

2015

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Epigenetics, and especially DNA methylation, have recently become provocative biological explanations for early-life environmental effects on later health. Despite the large increase in papers on the topic over the last few years, many questions remain with regards to the biological feasibility of this mechanism and the strength of the evidence to date. In this review, we examine the literature on early-life effects on epigenetic patterns, with special emphasis on social environmental influences. First, we review the basic biology of epigenetic modification of DNA and debate the role of early-life stressful, protective, and positive environments on gene-specific, system-specific, and whole-genome epigenetic patterns later in life. Second, we compare the epigenetic literatures of both humans and other animals and review the research linking epigenetic patterns to health in order to complete the mechanistic pathway. Third, we discuss physical environmental and social environmental effects, which have to date, generally not been jointly considered. Finally, we close with a discussion of the current state of the area’s research, its future direction, and its potential use in pediatric health.

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Section: Dna Methylationmentioning

confidence: 99%

DNA methylation, early life environment, and health outcomes

2015

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“…To determine the impact of EE on transgenerational versus cumulative ancestral stress, the design used (1) a lineage of transgenerational prenatal stress in which the parental generation but not the F1-F3 generations experienced stress, and (2) a lineage of multigenerational prenatal stress, in which each the parental and the offspring generations experienced gestational stress682425. The F3 generation is of particular relevance because it is the first generation in the maternal lineage that is not directly exposed to prenatal stress and therefore changes may be considered programmed through epigenetic inheritance26.…”

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confidence: 99%

Environmental Intervention as a Therapy for Adverse Programming by Ancestral Stress

McCreary

Erickson

Hao

et al. 2016

Sci Rep

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Ancestral stress can program stress sensitivity and health trajectories across multiple generations. While ancestral stress is uncontrollable to the filial generations, it is critical to identify therapies that overcome transgenerational programming. Here we report that prenatal stress in rats generates a transgenerationally heritable endocrine and epigenetic footprint and elevated stress sensitivity which can be alleviated by beneficial experiences in later life. Ancestral stress led to downregulated glucocorticoid receptor and prefrontal cortex neuronal densities along with precocious development of anxiety-like behaviours. Environmental enrichment (EE) during adolescence mitigated endocrine and neuronal markers of stress and improved miR-182 expression linked to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) regulation in stressed lineages. Thus, EE may serve as a powerful intervention for adverse transgenerational programming through microRNA-mediated regulation of BDNF and NT-3 pathways. The identification of microRNAs that mediate the actions of EE highlights new therapeutic strategies for mental health conditions and psychiatric disease.

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“…In those brain regions the number of neurons expressing Ndn is clearly less than in wild-type animals and variability of Ndn expression amongst the Ndn+m/−p offspring was linked to both maternal genotype and gender, being additive factors. A Ndn+m/−p mouse with a +/+ or Ndn+m/−p mother (a mouse who has inherited a wild-type Ndn allele from her grandmother) is predisposed to the highest level of expression and to a greater inter-individual variability, a phenomenon referred to as transgenerational epigenetic inheritance [31]. In contrast, paternal genotype has no impact.…”

Section: Discussionmentioning

confidence: 99%

Stochastic Loss of Silencing of the Imprinted Ndn/NDN Allele, in a Mouse Model and Humans with Prader-Willi Syndrome, Has Functional Consequences

et al. 2013

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Genomic imprinting is a process that causes genes to be expressed from one allele only according to parental origin, the other allele being silent. Diseases can arise when the normally active alleles are not expressed. In this context, low level of expression of the normally silent alleles has been considered as genetic noise although such expression has never been further studied. Prader-Willi Syndrome (PWS) is a neurodevelopmental disease involving imprinted genes, including NDN, which are only expressed from the paternally inherited allele, with the maternally inherited allele silent. We present the first in-depth study of the low expression of a normally silent imprinted allele, in pathological context. Using a variety of qualitative and quantitative approaches and comparing wild-type, heterozygous and homozygous mice deleted for Ndn, we show that, in absence of the paternal Ndn allele, the maternal Ndn allele is expressed at an extremely low level with a high degree of non-genetic heterogeneity. The level of this expression is sex-dependent and shows transgenerational epigenetic inheritance. In about 50% of mutant mice, this expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. In wild-type brains, the maternal Ndn allele is never expressed. However, using several mouse models, we reveal a competition between non-imprinted Ndn promoters which results in monoallelic (paternal or maternal) Ndn expression, suggesting that Ndn allelic exclusion occurs in the absence of imprinting regulation. Importantly, specific expression of the maternal NDN allele is also detected in post-mortem brain samples of PWS individuals. Our data reveal an unexpected epigenetic flexibility of PWS imprinted genes that could be exploited to reactivate the functional but dormant maternal alleles in PWS. Overall our results reveal high non-genetic heterogeneity between genetically identical individuals that might underlie the variability of the phenotype.

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The secret language of destiny: stress imprinting and transgenerational origins of disease

Cited by 38 publications

References 167 publications

DNA methylation, early life environment, and health outcomes

DNA methylation, early life environment, and health outcomes

Environmental Intervention as a Therapy for Adverse Programming by Ancestral Stress

Stochastic Loss of Silencing of the Imprinted Ndn/NDN Allele, in a Mouse Model and Humans with Prader-Willi Syndrome, Has Functional Consequences

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