Protein-Based Inheritance: Epigenetics beyond the Chromosome

Abstract

Epigenetics refers to changes in phenotype that are not rooted in DNA sequence. This phenomenon has largely been studied in the context of chromatin modification. Yet many epigenetic traits are instead linked to self-perpetuating changes in the individual or collective activity of proteins. Most such proteins are prions (e.g., [PSI⁺], [URE3], [SWI⁺], [MOT3⁺], [MPH1⁺], [LSB⁺], and [GAR⁺]), which have the capacity to adopt at least one conformation that self-templates over long biological timescales. This allows them to serve as protein-based epigenetic elements that are readily broadcast through mitosis and meiosis. In some circumstances, self-templating can fuel disease, but it also permits access to multiple activity states from the same polypeptide and transmission of that information across generations. Ensuing phenotypic changes allow genetically identical cells to express diverse and frequently adaptive phenotypes. Although long thought to be rare, protein-based epigenetic inheritance has now been uncovered in all domains of life.

Keywords: epigenetic inheritance; prions.

Figure 1. Transgenerational Stability of Different Modes of Epigenetic Inheritance

Conversion between states is indicated by color changes, with the ratio of different colored populations approximating the relative stability of each mode of inheritance. Approximate mitotic stability in terms of number of generations for which a particular mode of inheritance persists are noted above arrows spanning environmental input and mitosis. Meiotic inheritance is indicated by the color of progeny in the final column and the accompanying text.

Figure 2. Protein-based Epigenetic Inheritance Impacts Diverse Aspects of Biology

Each panel illustrates a different example of protein-based mechanisms of inheritance. [PSI⁺]: the yeast translation termination factor Sup35 normally ensures faithful translation termination by the ribosome. However, when Sup35 is sequestered into an oligomeric prion state, the fidelity of termination is reduced. This leads to the inclusion of variants in 3’ UTRs (denoted by star). Consequently, phenotypic diversity of the population is increased. [GAR⁺]: fermentative growth of yeast produces ethanol that helps to kill bacterial competitors (noted by X’s). However, certain bacteria secrete small molecules (e.g. lactic acid) that can lead to induction of the [GAR⁺] prion. This heritably shifts the metabolism of yeast, reducing ethanol output and increasing capacity for growth on complex carbohydrates. CPEB: upon serotonin signaling CPEB oligomerizes with RNA in a self-templating complex, leading to long-term memory facilitation.

Figure 3. Self-templating Conformational Conversion as a Form of Bistability and Hysteresis

A, Schematic for conformational conversion of prion states and chaperone mediated production of prion seeds. Because prion conformers self-template in the presence of chaperones, they create an autonomous positive feedback loop dependent on the prion protein alone. Native monomeric protein (left) can be converted to the prion conformer by seeding (top), resulting in the formation of oligomeric prion conformers (right). Prion oligomers can be disrupted by chaperone activity, liberated seeds to template further conversion of native monomers. B, Bistability arising from autonomous positive feedback of prion conformers creates hysteresis. Prion seeding may also provide an ultrasensitive response where a non-linear increase in prion conversion follows rapidly once seeds are formed. The system exhibits hysteresis and the prion conformation is stable even in the absence or lesser extent of stimulus. In the context of transcriptional control, this could robustly insulate two states, ‘on’ and ‘off’ (see right-hand side of panel), from small changes in stimulus, while still permitting rapid interconversion in response to directed triggers.