Epigenetic transgenerational inheritance of altered stress responses

A fantastic article on epigenetics. Please download the pdf file to read the full article.

Phenotype is determined by both inherited and experienced factors. Traditionally, the former are regarded as a result of genetic inheritance, and the latter encompass events in the individual’s personal life history. Study of how the environment shapes the phenotype was initially referred to as “epigenesis” (1) and later termed “epigenetics” by Waddington (2). The current definition for epigenetics used in this study is “molecular factors or processes that regulate genome activity independent of DNA sequence and are mitotically stable” (3). The model used in the current study involves an epigenetic transgenerational inheritance of a behavioral phenotype (4) induced by an environmental toxicant (5) and transmitted through the germ line, involving a permanent alteration in the sperm epigenome (i.e., DNA methylation) (6). The epigenetic transgenerational inheritance of this altered sperm epigenome modifies the subsequent development and epigenomes of all cells and tissues, including the brain, to promote phenotypic variation (7). Although no direct epigenetic measurements were made in the current study, the epigenetic model and role of epigenetics in development provides the molecular basis of the observations presented.

The development of brain and behavior involves at least two distinct epigenetic programming mechanisms (3, 8). “Germ line-dependent” epigenetic change occurs when the modified epigenome is permanently incorporated into the germ line to manifest each generation in the absence of the causative agent. “Context-dependent” epigenetic change occurs when the environmental factors that bring about the epigenetic modification persist in the environment. Most research in epigenetics today falls within this context-dependent category. Although both have been attributed with “generational” properties, only germ line-dependent epigenetic modification is epigenetic transgenerational inheritance (5, 7). The life-history approach to the study of behavioral development emphasizes both the continuity and interplay between the internal and external environmental characteristic of the specific life stages. Most research on the effects of stress has focused on the earliest life stages (fetus and neonate) or adulthood, with relatively few studies on adolescence (9?–11). It is during this period that adrenarche and pubarche occur and the individual graduates from dependence to independence, assuming the properties of maturity. Stress experienced during adolescence has enduring effects, including neural remodeling, sensitivity to drugs of abuse, impaired learning and memory, and altered emotional behaviors in adulthood (12??–15). The current study shows that the effects of chronic restraint stress (CRS) during adolescence on the adult physiological, behavioral, and neural phenotypes become more profound when considered in the context of epigenetic transgenerational inheritance.

We investigated this complex phenotypic response with a unique statistical approach for multidimensional phenotype analysis (16). Systems biology attempts to understand how molecular- to organism-level processes are involved in the emergence of complex phenotypes. Emergence was originally formulated by Weiss (17, 18) to mean “phenotypes, and the mechanisms that underlie them, depend on, and subordinate to, the law which rules the complex as a unit.” Systems biology approaches have recently been used to examine the phenotype at the molecular level of genetics or epigenetics (19). The current study tests the hypothesis that a combination of an environmentally induced epigenetic transgenerational inheritance (lineage) and context-dependent stress (stress) interact and promote alterations in brain development and genome activity (gene networks) that alter the adult phenotype at all levels.