DNA is the repository of genetic information that contains the instructions to generate living organisms, and is the predominant carrier of biological inheritance through mitosis and meiosis. However, the interpretation of genetic information, ultimately determining the characteristics of individuals (i.e. the phenotype), is finely regulated through multiple coordinated mechanisms, including the interaction between the genome and the environment. During the past ∼30 years, genetic and molecular studies have defined the machinery responsible for many facets of so-called epigenetic regulation: from the enzymes involved in the biogenesis, interpretation, and clearance of epigenetic marks, to the mechanisms of epigenetic inheritance through cell division and the functions of epigenetic marks in gene expression regulation.

The molecular players central to epigenetic inheritance — including (but not limited to) DNA methylation (DNAme), histone post-translational modifications (PTMs) and variants, and short and long noncoding RNAs — play key roles in both somatic and germ cells, albeit with quite distinctive functions in these populations. In mammals, for instance, DNAme patterns at imprinted genomic regions are established during gametogenesis in a parent-of-origin manner, carried in the gametes at fertilization, and are essential for subsequent development of the resulting embryo 1, 2, 3, 4.

Epigenetic marks, by their dynamic and reversible nature, grant living systems the ability to respond to environmental fluctuations and modulate their genetic output without permanent changes to the underlying DNA content. This has led to a re-evaluation of the potential for ancestral environments to influence phenotypic traits in the next meiotic generation through epigenetic changes, sparking a great deal of debate, particularly in mammals. Mechanistically, in order for parental exposures to program offspring phenotypes, they must elicit a change in the germline epigenome, which then needs to survive the near-global epigenetic reprogramming taking place during early development.

The last two decades have seen the resurgence of the field of parental effects, and studies in a variety of model organisms have documented evidence of transmission of so-called epialleles (i.e. alternative epigenetic states of a genetically identical locus) between generations. While some epialleles arise spontaneously in populations in an apparently stochastic manner, an increasing diversity of signal-induced changes to the epigenome continue to be appreciated as contributors to biological inheritance. Specifically, when environmentally modulated epigenetic information is passed through gametes and elicits a phenotypic output in the progeny of exposed organisms, we refer to this phenomenon as intergenerational epigenetic inheritance (IEI, from parental to first filial generation). Otherwise, we define transgenerational epigenetic inheritance (TEI) when a phenotypic change persists beyond F1 to organisms that were not directly exposed to the initial stimulus.

In this Opinion, we focus on recent findings and emergent IEI/TEI paradigms in animals and highlight some of the ‘classics’ of TEI in light of new discoveries. We discuss epigenetic modalities and mechanisms associated with TEI phenomena, touch upon the challenges of the study of epigenetic information transfer between generations, and introduce emergent findings regarding parental effects in humans.