Epigenetic Inheritance: Concepts, Mechanisms and Perspectives

Abstract

Parents' stressful experiences can influence an offspring's vulnerability to many pathological conditions, including psychopathologies, and their effects may even endure for several generations. Nevertheless, the cause of this phenomenon has not been determined, and only recently have scientists turned to epigenetics to answer this question. There is extensive literature on epigenetics, but no consensus exists with regard to how and what can (and must) be considered to study and define epigenetics processes and their inheritance. In this work, we aimed to clarify and systematize these concepts. To this end, we analyzed the dynamics of epigenetic changes over time in detail and defined three types of epigenetics: a direct form of epigenetics (DE) and two indirect epigenetic processes-within (WIE) and across (AIE). DE refers to changes that occur in the lifespan of an individual, due to direct experiences with his environment. WIE concerns changes that occur inside of the womb, due to events during gestation. Finally, AIE defines changes that affect the individual's predecessors (parents, grandparents, etc.), due to events that occur even long before conception and that are somehow (e.g., through gametes, the intrauterine environment setting) transmitted across generations. This distinction allows us to organize the main body of epigenetic evidence according to these categories and then focus on the latter (AIE), referring to it as a faster route of informational transmission across generations-compared with genetic inheritance-that guides human evolution in a Lamarckian (i.e., experience-dependent) manner. Of the molecular processes that are implicated in this phenomenon, well-known (methylation) and novel (non-coding RNA, ncRNA) regulatory mechanisms are converging. Our discussion of the chief methods that are used to study epigenetic inheritance highlights the most compelling technical and theoretical problems of this discipline. Experimental suggestions to expand this field are provided, and their practical and ethical implications are discussed extensively.

Keywords: epigenetic; inheritance; methylation; microRNA; psychopathology; stress; transgenerational; transmission.

Figure 1

Transgenerational epigenetic inheritance. According to the classical definition of transgenerational epigenetic inheritance, environmental triggers that hit pregnant female individuals (F0) can affect “directly” not only the first new generation (F1), but also its germ cells that represent the second generation (F2). For this reason, only changes in F3 can be due “purely” to epigenetic inheritance. The male germline, instead, can be affected only for one generation, allowing observing epigenetic inheritance already at F2.

Figure 2

Epigenetics through the Minkowskian cone. Epigenetic changes and related environmental factors visualized in 4D Minkowskian space, assuming conception as our arbitrarily chosen observation point, the zero of the system. Across indirect epigenetics (AIE) includes all those adaptations in parental life that precede conception; within indirect epigenetics (WIE) describes all those changes that take place during the gestational period and, finally, direct epigenetics (DE) describes all those plastic processes that can occur after birth. Although these processes are strongly interconnected and can overlap on multiple levels in a complex real system, here they are treated as discrete and sequential, for the sake of clarity.

Figure 3

Methylation and demethylation. Methylation is a regulatory process of gene expression, catalyzed by DNA methyltransferase enzymes, owing to the addition of a methyl group to the fifth position of a cytosine. DNA methyltransferases 1 (DNM1) is mainly involved in maintenance methylation that restores symmetric DNA methylation patterns after DNA replication. DNM3A, DNMTB and DNMTL, instead, are involved in the catalytic process that produces de novo methylation by adding methyl groups to unmethylated DNA strands. Methylation processes can be reverted by two mechanisms: passive demethylation due to loss of methylation across consecutive DNA replications; active demethylation mediated by ten-eleven translocation (TET) proteins.

Figure 4

Biomarker reset. The elimination and restoration of methylation markers happen in two steps. A first, active demethylation takes place in parental gametes, right after fertilization. This process is mostly active—and therefore faster: it is completed by the first cell division—for paternally inherited genome, while maternal pronucleus is slowly demethylated by passive diffusion across replications. This first global erasure of methylation marks spares only imprinted loci and some retrotransposons, and it is deemed to establish cellular totipotency. After the implantation of the developing blastocyst, a first de novo methylation wave begins, driving the crucial process of cellular differentiation. At the beginning of gametogenesis, when primordial germ cells start to migrate, a second demethylation takes place: gametes’ chromatin is globally demethylated, also including imprinted loci. After sex-determination, gametogonia are remethylated by a second wave of de novo methylation, which is higher (90%) and faster (it is mostly complete before birth) for male gametes and slower (40%) and lower (it does not end until puberty) for female gametes. Imprinting patterns are usually reestablished during this phase. The established patterns can be altered by direct or indirect experiences, particularly during gestation and right after birth. These processes depend on the activity of several epigenetic enzymes, among which DNA methyltransferases (DNMTs) and TETs are prominent. The regulation of these processes by non-coding RNA (ncRNA), has also been established.

Figure 5

From in vitro fertilization (IVF) to fostering. Here, we schematize the suggested ideal model that could help define with great precision the spacetime of a given epigenetic factor’s action. Once its role in fetal programming has been established, investigating its possible play in transgenerational epigenetic inheritance processes might be easier. See the text for more details.