Molecular insights into the transgenerational inheritance of stress memory

There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.

Alternative models for transgenerational epigenetic inheritance:Molecular psychiatry beyond mice and man

Mental illness remains the greatest chronic health burden globally with few inroads having been made despite significant advances in genomic knowledge in recent decades.The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations,and that has to be supported by a continuous growth in knowledge.The majority of neuropsychiatric symptoms reflect complex geneenvironment interactions,with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms.It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stressrelated behavioural phenotypes in both paternal and maternal lineages,providing further supporting evidence for heritability in humans.However,unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions.While rodents will remain the dominant model system for preclinical studies(especially for addressing complex behavioural phenotypes),there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models.Here,we will discuss the utility and advantages of two alternative model organisms–Caenorhabditis elegans and Drosophila melanogaster-and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.

Thermal conditioning of quail embryos has transgenerational and reversible long‑term effects

Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubation temperature.However,because of their likely epigenetic origin,thermal manipulation effects may last more than one generation with consequences for the poultry industry.In this work,a multigenerational and transgenerational analysis of thermal manipulation during embryogenesis was performed to uncover the long-term effects of such procedure.Results Thermal manipulation repeated during 4 generations had an effect on hatchability,body weight,and weight of eggs laid in Japanese quails,with some effects increasing in importance over generations.Moreover,the effects on body weight and egg weight could be transmitted transgenerationally,suggesting non-genetic inheritance mechanisms.This hypothesis is reinforced by the observed reversion of the effect on growth after five unexposed generations.Interestingly,a beneficial effect of thermal manipulation on heat tolerance was observed a few days after hatching,but this effect was not transgenerational.Conclusions Our multigenerational study showed that thermal conditioning of quail embryos has a beneficial effect on post-hatch heat tolerance hampered by transgenerational but reversible defects on growth.Assuming that no genetic variability underlies these changes,this study provides the first demonstration of epigenetic inheritance of traits induced by environmental temperature modification associated with long-term impacts in an avian species.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons.Here we explored how gestational exposure to dexamethasone,a synthetic glucocorticoid commonly used in clinical practice,has lasting effects on offspring's learning and memory.Adult offspring rats of prenatal dexamethasone exposure(PDE)displayed significant impairments in novelty recognition and spatial learning memory,with some phenotypes maintained transgenerationally.PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations,and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory,but these changes failed to carry over to offspring of F5 and F7 generations.Mechanistically,altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission,which might be related to oocyte-specific high expression and transmission of miR-133a-3p.Together,PDE affects hippocampal excitatory synaptic transmission,with lasting consequences across generations,and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Environmentally Induced Paternal Epigenetic Inheritance and Its Effects on Offspring Health

Increasing evidences indicate that chronic diseases in offspring may be the result of ancestral environmental exposures. Exposures to environmental compounds in windows of epigenetic susceptibility have been shown to promote epigenetic alterations that can be inherited between generations. DNA methylation, histone modifications, and noncoding RNAs are sound mechanistic candidates for the delivery of environmental information from gametes to zygotes. This review focuses mainly on paternal exposures and assesses the risk of epigenetic alterations in the development of diseases, providing insights into relationships between aberrant sperm epigenetic patterns and offspring health. Elucidation of the mechanisms underlying environmental epigenetic information that survive from epigenetic reprogramming and its transmission to future generations may hold a great promise for providing therapeutic targets for epigenetic diseases associated with environmental exposures.

Systematic characterization of small RNAs associated with C.elegans Argonautes

Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans.Canonical s RNAs in C.elegans are mi RNAs,small interfering RNAs including 22G-RNAs and 26G-RNAs,and 21U-RNAs,which are C.elegans pi RNAs.Previous studies have only covered some of these Argonautes for their s RNA partners,and thus,a systematic study is needed to reveal the comprehensive regulatory networks formed by C.elegans Argonautes and their associated s RNAs.We obtained in situ knockin(KI)strains of all C.elegans Argonautes with fusion tags by CRISPR/Cas9 technology.RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the s RNA profiles of individual Argonautes.The s RNA partners for each Argonaute were then analyzed.We found that there were 10Argonautes enriched mi RNAs,17 Argonautes bound to 22G-RNAs,8 Argonautes bound to 26G-RNAs,and 1 Argonaute PRG-1bound to pi RNAs.Uridylated 22G-RNAs were bound by four Argonautes HRDE-1,WAGO-4,CSR-1,and PPW-2.We found that all four Argonautes played a role in transgenerational epigenetic inheritance.Regulatory roles of the corresponding Argonaute-s RNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated.In this study,we portrayed the s RNAs bound to each functional Argonaute in C.elegans.Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C.elegans Argonautes and s RNAs.The s RNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.