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.

A bacteria-based genetic assay detects prion formation

“…A defining property of prion-forming proteins is their ability to exist in alternative conformational states, at least one of which, the prion form, is self-perpetuating (8)(9)(10)(11). Typically, prionforming proteins adopt an amyloid fold in their prion conformations, thus forming fibrillar aggregates (6,10).…”

Protein assembly systems in natural and synthetic biology

“…IDRs are protein sequences that do not adopt a single three-dimensional structure, but instead endow proteins with flexibility to adopt a range of states, from unstructured to partially structured [6]. Due to this flexibility, IDRs can enable proteins to engage multiple partners and participate in the different types of interactions that facilitate initiation of protein assembly, e.g., (1) specific interactions among or between folded domains and unfolded sequences [7][8][9] and (2) non-specific weak interactions among IDRs [10,11]. Depending on the relative strength and avidity of these interactions, as well as other factors such as the physicalchemical state of the cellular environment, a broad spectrum of assembly phenomena can arise ( Fig.…”

“…But in part due to the development of new techniques to study protein aggregates ( Table 2), we are gaining a new appreciation and understanding of their non-pathological roles. Protein aggregates play positive functions in a variety of cellular processes, including gene regulation [126,127], signaling [76,128,129], memory storage [56,130,131], DNA repair [132], cell fate decisions [130,[133][134][135], and even evolution [2]. These examples should serve as inspiration for synthetic biologists aiming to purposefully manipulate information flow in living systems ( Fig.…”

“…Amazingly, many of these critical molecules readily aggregate and assemble inside of living cells through interactions amongst unfolded and folded domains. This can occur aberrantly and lead to disease; but there is also accumulating evidence that aggregation phenomena can be regulated by the cell and used to carry out important and beneficial biological functions ranging from molecular scaffolding to memory [1][2][3][4]. Moreover, when designing synthetic cellular systems using synthetic biology, we argue that protein aggregation may be viewed as a "feature" rather than a "bug", and that self-assembling elements possess unique properties that can be exploited to engineer new biological functions [5].…”

Improvement of the memory function of a mutual repression network in a stochastic environment by negative autoregulation

“…Memory is ubiquitous in biological systems [1][2][3][4]. Characterized by a continued response to a transient stimulus [5], cellular memory has been found to aid in the robust control of diverse biological functions such as synaptic plasticity [6], differentiatio n [7,8], cell cycle transition [9], or gene regulation [10].…”