Improving the odds of survival: transgenerational effects of infections

Abstract

Recent studies argue for a novel concept of the role of chromatin as a carrier of epigenetic memory through cellular and organismal generations, defining and coordinating gene activity states and physiological functions. Environmental insults, such as exposures to unhealthy diets, smoking, toxic compounds, and infections, can epigenetically reprogram germ-line cells and influence offspring phenotypes. This review focuses on intergenerational and transgenerational epigenetic inheritance in different plants, animal species and humans, presenting the up-to-date evidence and arguments for such effects in light of Darwinian and Lamarckian evolutionary theories. An overview of the epigenetic changes induced by infection or other immune challenges is presented, and how these changes, known as epimutations, contribute to shaping offspring phenotypes. The mechanisms that mediate the transmission of epigenetic alterations via the germline are also discussed. Understanding the relationship between environmental fluctuations, epigenetic changes, resistance, and susceptibility to diseases is critical for unraveling disease etiology and adaptive evolution.

Keywords: Epigenetic Memory; Epigenetics; Evolution; Infections; Transgenerational Epigenetic Inheritance.

Figure 1. A schematic overview of intergenerational versus transgenerational epigenetic inheritance via the maternal and the paternal germline.

Insults of environmental exposures on a mother (F0) during gestation can directly influence the fetus (F1) and its developing germ cells (F2). In the same way, environmental stressors can directly affect the male or female before gestation (F0) and their germline (F1). These phenotypic effects observed after direct exposure represent intergenerational epigenetic inheritance (light blue). Transgenerational epigenetic inheritance represents the phenotypic changes observed on F2 generation offspring or on F3 generation offspring and beyond in the case of a gestating mother induced after indirect exposure to environmental stimuli (light pink).

Figure 2. Epigenetic mechanisms that mediate intergenerational and transgenerational transmission of traits.

From left to right the Figure shows the different types of organisms, the immune triggers leading to the epigenetic reprogramming, the molecules and mediators involved in the establishment of the epigenetic changes and the transmission of the epigenetic memory to the offspring, and the phenotypic effects observed across multiple generations. (A) In plants, the first line of defense includes Volatile Organic Compounds (VOCs) emission upon Pathogen-Associated Molecular Patterns and/or Damage-Associated Molecular Patterns (DAMPs) engagement. siRNA-guided DNA methylation and chromatin modification contribute to epigenetic regulation and influence gene expression patterns and genome stability. Especially de novo methylation of DNA after exposure to DAMPs or PAMPs is involved in the establishment of epigenetic memory in the next generation. (B) DNA methyltransferase 2 (Dnmt2) is one of the key enzymes of epigenetic regulation in invertebrates. Dnmt2 can lead to immune-related gene methylation and tRNA methylation by the transfer of methyl groups. (C) In rodents, sperm small RNAs are central mediators of the establishment and transfer of epigenetic information. DNA methylation and histone modifications on both egg and sperm are also involved in epigenetic inheritance mechanisms. (D) DNA methylation of genes related to immune function and neurodevelopmental pathways leading to a tightly packed chromatin structure and thus limiting gene expression have been demonstrated in humans after viral infections.

Figure 3. Epigenetic mechanisms that mediate transgenerational epigenetic inheritance through sperm (small RNAs) and through egg (DNA methylation).

(A) Male mice experimentally infected with tachyzoites of Toxoplasma gondii showed changes in sperm small RNAs. Sperm was retrieved and the total small RNA was isolated and injected into the pronucleus of fertilized eggs using micro-injecting method. Surviving zygotes developed in cell cultures and the embryos were implanted into surrogate mothers. The resulting male and female offspring recapitulated the behavioral changes of first and second-generation offspring from T. gondii-infected fathers. (B) A DNA methylation-edited mouse was generated using mouse embryonic stem cells (mESCs), in which targeted CpG islands in promoters of two metabolism-related genes were methylated and silenced. The DNA methylation-edited mESCs were microinjected into 8-cell embryos (epiblast stage) to create a mosaic mouse with normal and methylation-edited cells. The induced DNA methylation and the associated silencing of the specific gene expression stood stably transferred through maternal and paternal germlines across at least 4 generations.

Figure 4. Overview of the species phylogeny of the organisms in which intergenerational and/or transgenerational effects have been demonstrated.

The phylogenetic tree includes 2 plant species: Linaria vulgaris and Arabidopsis thaliana, 10 invertebrate species: Plodia interpunctella, Galleria mellonella, Manduca sexta, Tribolium castaneum, Tenebrio molitor, Bombus terrestris, Culex pipiens, Daphnia magna, Artemia franciscana and Caenorhabditis elegans, and 4 vertebrate species: Mus musculus, Rattus norvegicus, Onychomys and Homo sapiens.