159 6 REPRODUCTIONREVIEW Mechanisms of epigenetic inheritance of variable traits through the germline Eduard Casas1,2,3 and Tanya Vavouri1,3 1Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC- IGTP), Badalona, Spain, 2Doctoral Programme in Biomedicine, Universitat de Barcelona, Barcelona, Spain and 3Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain Correspondence should be addressed to T Vavouri; Email: [email protected] Abstract During the past half century, evidence for inheritance of variable traits has accumulated from experiments in plants and animals and epidemiological studies in humans. Here, we summarize some of the reported cases of epigenetic inheritance and the proposed mechanisms involved in the transmission of non-genetic information between generations in plants, nematodes, flies and mammals. It has long been accepted that information is epigenetically inherited in plants. Although many questions regarding the underlying mechanisms remain to be answered, it is now evident that epigenetic mechanisms are also responsible for the transmission of phenotypes in animals. We highlight similarities and differences between models and species. Reproduction (2020) 159 R251–R263 Introduction high maternal care towards mouse pups induces increased glucocorticoid gene expression, which loses Epigenetics refers to mechanisms that maintain memory promoter DNA methylation and gains active chromatin of gene expression or phenotype without a change in DNA state that is maintained to adulthood and is associated sequence (Deans & Maggert 2015). Such mechanisms, with less stress reactive behaviour in adult mice (Weaver for example, underlie the permanent repression of et al. 2004). However, in almost all organisms, during transposons in all cells of an organism, parent-of-origin gametogenesis and embryogenesis, most acquired dependent expression of imprinted genes and memory epigenetic information is erased and reset, resulting in a of cell identity during cell divisions, as well as long- ‘clean slate’ at the beginning of life of a new individual term responses to external stimuli. Although memory of through processes collectively referred to as epigenetic transposon repression, imprinting and cell identity lead reprogramming. to similar gene expression patterns between individuals Memory of some responses to external stimuli can (if we exclude differences due to genetic and stochastic escape epigenetic reprogramming and be transmitted variation), memory of responses to external stimuli lead through the germline to the next generation. The to divergent gene expression patterns and phenotypes. idea that acquired traits can be inherited between In this review, we discuss models and mechanisms of generations has fascinated scientists for more than 200 inheritance of variable or acquired traits specifically years (since Jean-Baptiste Lamarck) but it was not until through the germline. the 1900s that loci that transmit information between Responses to external stimuli can be maintained for generations were discovered and that some aspects weeks, months or even years of the life of an organism. of the underlying mechanisms started to become A classic example of epigenetics is the dependance apparent. To date, there are hundreds of reported cases of early flowering on past prolonged-exposure to cold of potential epigenetic inheritance from very diverse weather – a phenomenon known as vernalization. organisms (Jablonka & Lamb 1999). In most cases, This is because cold temperatures during winter cause the mechanism of inheritance is completely unknown increased chromatin repression at the locus that and for some of them inheritance will turn out to be contains a key repressor of flowering, thus enabling by genetics and other by non-epigenetic mechanisms. the activation of flowering genes in spring (reviewed Nevertheless, during the past two decades, carefully in Mylne et al. 2004). Long-term responses are also controlled experiments have provided very strong common in animals, including mammals. For example, © 2020 Society for Reproduction and Fertility https://doi.org/10.1530/REP -19-0340 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 08:36:23PM via free access -19-0340 R252 E Casas and T Vavouri Models and mechanisms of epigenetic inheritance Box 1: Definitions in plants Intergenerational and transgenerational epigenetic inheritance: Both terms refer to the transmission of a variable trait or In plants, the germline differentiates from somatic cells response through the germline by epigenetic mechanisms. in the adult which, after responding to environmental Transgenerational epigenetic inheritance refers to inheritance stimuli, can theoretically transmit memory of the response of a trait for multiple generations, which requires that the trait to the next generation. Still, in plants (as in animals), be able to escape reprogramming in both the germline and the epigenetic reprogramming resets gene expression state early embryo. Intergenerational epigenetic inheritance refers to during sexual reproduction when DNA methylation and inheritance of a trait that lasts for one to two generations only, and it implies that memory of the trait or response is erased in chromatin undergo significant remodelling (Kawashima the germline. & Berger 2014). Although chromatin is clearly important Epialleles: Refers to heritable alternative expression states of a for the maintenance of expression states during gene that are not caused by genetic variation. Epialleles can often mitotic division and has been implicated in epigenetic switch states after one or more generations during epigenetic inheritance in animals (as discussed subsequently), in reprogramming or in response to external stimuli (Rakyan et al. plants there is so far little evidence that it is involved in 2002). the transmission of acquired traits between generations. Histone marks: Nucleosomes contain histone variants and histone This does not mean that chromatin is not involved in post-translational modifications that form a combinatorial code epigenetic inheritance, but rather that its role has not associated with the active or repressed state. There are many histone modifications but the ones discussed in this review are been sufficiently explored so far. Instead, most research the following: histone H3 lysine four trimethylation (H3K4me3), in the field has been focused on DNA methylation. which is associated with promoters of genes that are either In plants, DNA methylation occurs at the CG, CHG active or that are inactive but poised for activation; histone H3 and CHH context (where H is C, A or T). During DNA lysine 9 di- or trimethylation (H3K9me2/3), which is associated replication, MET1 (the plant homologue of DNMT1) with repressed repeats and transgenes and histone H3 lysine 27 maintains methylation at CG sites, the H3K9me2- trimethylation (H3K27me3), which is predominantly linked to associated DNA methyltransferase CMT3 maintains repression of protein-coding genes during development. methylation at CHG sites and CMT2 and the RNA- directed DNA methylation (RdDM) pathway methylate support for the involvement of epigenetics in the cytosines at the asymmetric CHH sites (reviewed in inheritance of traits. Zhang et al. 2018a) (see Box 1 for a brief description of A number of mechanisms have been linked to the histone marks). There are multiple variations of the RdDM transmission of phenotypes between generations, pathway but the canonical one involves the transcription including parental behaviour, prions and microbiota, of a heterochromatic locus by the DNA-dependent RNA among others. Here, we focus on the molecular polymerase PolIV, the production of a dsRNA generated mechanisms most commonly studied in the field of by the RNA-dependent RNA polymerase RDR2, the epigenetics which are DNA methylation, chromatin and activity of the Dicer-like protein DCL3 which results small non-coding RNAs. Basic epigenetic mechanisms in the production of 24nt siRNAs that target nascent are broadly conserved in eukaryotes. However, there RNAs transcribed by PolV and cause de novo cytosine are also important differences. We have therefore methylation by DRM2. Methylation at the CG and CHG organized this review by model organism. For each context is stable through the plant life cycle, while DNA species, we start with a brief summary of relevant methylation at the CHH context at young transposons species-specific considerations such as the epigenetic undergoes two waves of reprogramming, once in the mechanisms active in the species and the time of early embryo and then again in the seedling (Mosher germline specification, both of which likely affect how et al. 2009, Calarco et al. 2012, Jullien et al. 2012, Bouyer and what kind of responses to environmental stimuli et al. 2017, Kawakatsu et al. 2017, Narsai et al. 2017). are transmitted between generations. We then discuss Maintenance of DNA methylation at CG and CHG sites some of the most prominent models of epigenetic thus provides the simplest and probably most common inheritance and what is currently known about the mechanism of epiallele inheritance (see Box 1 for a underlying mechanisms. We start the review with a definition of epiallele). Indeed, many loci that lose DNA brief overview of epigenetic inheritance