Transgenerational Epigenetic Inheritance in Animals

with abiotic and biotic components of their surroundings. Whereas many and perhaps most of the encounters pass with transient changes at the molecular and metabolic levels, some have a profound impact on the phenotypic appearance of an organism and, more importantly, on the phenotypic appearance of their progeny. Since genetic changes are rare and random in nature, their influence on species or/and population evolution, especially in higher eukaryotes, may not be as dramatic and important as it was believed to be. In contrast, environmentally induced transgenerational phenotypic changes, that is what epigenetics in its narrow sense is, are more likely to have an appreciable effect on stress adaptation and the process of microevolution. To date, there are many more definitions of epigenetics and transgenerational responses. Whether or not one appreciates a topic of transgenerational epigenetic responses and their heritable nature, there is still a substantial debate about the nature of these and other related phenomena. The current opinion article attempts to present several different views on transgenerational epigenetic inheritance in animals, including various definitions of this and other related terms. It proposes to standardize the meaning behind these definitions and suggests some minimum requirements for reporting transgenerational effects and transgenerational heritable effects of stress. First of all, what is epigenetics? There is substantial disagreement even over a simple (or not that simple) definition of the term epigenetics itself. The actual term “epigenetics” was first used by Conrad Hal Waddington, and in its strict meaning, it was supposed to describe the interaction between organisms and their environment that resulted in the appearance of a particular phenotype. Indeed, it is impossible nowadays to talk about epigenetics without considering its critical component – the interaction with environment. Also, since the emergence of epigenetics has been associated with the concept of “soft inheritance,” heritability of changes may be one of the requirements for the definition of epigenetics. One of the modern definitions of epigenetics suggests that epigenetics represents heritable changes in gene expression that do not involve changes in the genetic code. Again, the word “heritable” is there, which implies that changes must be observed in the progeny of an organism. Nowadays, epigenetic mechanisms include a variety of modifications such as DNA methylations, a vast plethora of histone modifications, and replacements of regular histones with histone variants, changes in chromatin structure as a consequence of differential binding of non-histone proteins, and, finally, the activity of various small noncoding RNAs. It is debatable whether the regulation of gene expression through small RNAs should be considered to be part of epigenetic regulation. There seems to be no clear position on that. In my interactions with many reviewers and editors encountered in the processes of submission/review to many journals, I noticed that the majority of scientists believe that the regulation of gene expression via small RNAs is part of epigenetic regulation. As summarized by Ho and Burggren (2010), the definition of epigenetics largely depends on whether the term is used by a molecular biologist, a geneticist, a developmental biologist, or an animal physiologist. The same is true for cell or epigenetic memory. The term transgenerational inheritance or heritability reflects changes at the cellular level (mitotic and meiotic), changes in population levels, or even behavioral level changes (Ho and Burggren, 2010). For further details of these definitions, I refer the reader to this review and the list of works cited. If we adhere to the opinion that a more narrow definition of epigenetics involves heritability of changes, we need to consider several other related definitions such as a transgenerational response, a transgenerational transfer, and transgenerational memory, all of which are believed to occur without changes in the genetic makeup. In the past, these more restricted terms that define epigenetics were referred to as “parental transfer,” “genomic imprinting,” and more recently “transgenerational memory” and “transgenerational response,” or “transgenerational plasticity” (reviewed in Ho and Burggren, 2010). Most of these terms emerged in an attempt to describe changes in the progeny of an organism exposed to stress. Frequently but not always, the progeny of stressed organisms acquired some beneficial traits such as the ability to respond to stress. Thus, transgenerational response can be defined as changes in physiology in response to stress of the progeny whose one parent was exposed to prior to fertilization. Are transgenerational effects always heritable? Although the transgenerational transfer or transgenerational memory may include many different factors that can be attributed to epigenetics, such as the pool of differentially expressed small RNAs either in the cytoplasm of the ovum or in the nucleus of both the ovum and sperm cells, some of the factors are not necessarily epigenetic in nature. For example, the accumulation of proteins and metabolites in the cytoplasm and organelles of maternal gametes in response to stress may significantly alter the development and phenotypic appearance of an organism. Such events are definitely part of a transgenerational response but are hardly epigenetic in nature. A broad definition of the transgenerational transfer implies the transfer of the phenotypic appearance into the progeny independently of genetic factors. In contrast, transgenerational epigenetic inheritance is the transfer of the phenotypic appearance as a result of the transfer of epigenetic marks. These epigenetic modifications are assumed to be solely responsible for phenotypic changes. Thus, heritability of transgenerational events may rely on, among other epigenetic events, DNA methylation, and histone Transgenerational epigenetic inheritance in animals