Epigenetic and transgenerational reprogramming of brain development

Abstract

Neurodevelopmental programming - the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development - requires tight regulation of transcriptional processes. During prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. Epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. Epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs.

Figure 1 |. Complex interactions between the maternal milieu, placenta and fetal compartments during gestation.

Fetal antecedents such as maternal dietary deficiencies, chronic stress or infection can promote endocrine disruptions in the maternal milieu, including increases in pro-inflammatory cytokines and stress hormones, and shifts in metabolic indices. In addition, these environmental exposures can indirectly alter placental development and function by changing local energy metabolism and lipid storage and metabolism. This can alter the transmission of key nutrients that are important for fetal growth and brain development, including growth factors and methyl donor nutrients such as folate and choline, which can affect fetal somatic and germ cell epigenetic programming. FFAs, free fatty acids; IGF, insulin-like growth factor; IGFBP, IGF-binding protein.

Figure 2 |. Modes of maternal and paternal transgenerational epigenetic transmission.

Several mechanisms for transgenerational epigenetic transmission are possible, asshown in the table, in which a red mouse indicates that the phenotype is shown in a particular generation, a | In utero somatic programming may affect tissue and brain development inthe fetus, initiating a developmental trajectory that results in an adult phenotype inthe first (F1) generation. However, this phenotype is not transmitted to the next generation, as there is no germ cell involvement. b | If in utero somatic programming is accompanied by changes in primordial germ cells, the phenotype will be transmitted to a second (F2) generation. In order for this to occur, germ cells must be exposed to a maternal insult during gestation. c | If the in utero exposure is able to alter epigenetic marks in the germ line of the F1 offspring and this reprogramming is able to withstand erasure and re-establishment during subseguent generations’ germ cell development, the phenotype will be perpetuated across generations withoutthe need for re-exposure to the original insult. This is defined as a truly transgenerational epigenetic programming. d | Transgenerational phenotypes may also occurthrough a repeated maternal effect by which programming during gestation or through exposure to altered maternal behaviours results in an adult phenotype that is only found in the maternal lineage. In order for this to occur, the offspring must be re-exposed to the insult in each generation to promote the continuation of the phenotype from the dam. This trait would not be passed through a paternal lineage. e | Transgenerational programming through a paternal lineage originating from an initial exposure inthe male reguires establishment or reprogramming of epigenetic marks in the sperm. Adapted with permission from REF , Elsevier.

Figure 3 |. Programming of phenotypes and disease risk can skip generations.

Maternal stress or dietary insults can generate signals, in the form of changes in the hormonal milieu, that are transmitted from the maternal to the fetal compartment via the placenta. The resulting maternal programming of fetal somatic tissues can lead to changes in long-term health outcomes in the first generation (F1). Furthermore, in utero exposure can also occur for the primordial germ cells that will give rise to the second generation (F2), as these germ cells are also present and undergo reprogramming during embryonic development. If the exposure does not produce a detectable effect on somatict issues but is still able to reprogramme epigenetic marks in the germ cell, a phenotype could effectively arise in the F2 generation that was not present in the F1 generation, thus having the appearance of ‘skipping a generation’. Adapted with permission from REF , Elsevier.

Figure 4 |. Windows of vulnerability to environmental reprogramming in spermatogenesis.

The figure shows the stages of spermatogenesis and sperm maturation, highlighting the periods in which environmental exposures can reprogramme epigenetic marks. Active transcription and storage of RNA is ongoing through the spermatogonium, spermatocyte and spermatid stages. However, once compaction of paternal DNA has occurred, which involves replacing the majority of histones with protamines, there is not a clear mechanism by which epigenetic marks can be further altered in the mature sperm. This suggest sthat an environmental exposure must occur within a sensitive time period of spermatogenesis in order to pass on a new or reprogrammed epigenetic mark to future offspring. In most mammals, complete spermatogenesis occurs in 6–8 weeks, by which point sperm are present in the epididymis for final maturation processes. The time between chromatin compaction and the transit of mature sperm to the epididymis is at least 10 days, during which time epigenetic and transcriptional machineries are no longer active. However, the secretion of exosomes and other factors that interact with the maturing sperm in the epididymis may impart lasting epigenetic marks, such as microRNAs. Figure is reproduced from BaleT. Lifetime stress experience: transgenerational epigenetics and germ cell programming. Dialogues Clin. Neurosci. 2014;16:297–305 (REF. 179), with the permission of © AICH-Servier Research Group, Suresnes, France, and adapted from REF. , Nature Publishing Group.