Epigenetic Role of Prions

From Icamipedia

1 Introduction
2 Epigenetics
3 Role of Prions in Epigenetics
4 References
5 Links

Introduction

Prions, infectious proteins, have been linked to such maladies as Cruetzfeldt-Jakob Disease, Gerstmann-Sträussler-Scheinker disease, Fatal Familial Insomnia, Kuru, Scrapie, and Bovine Spongioform Encephalopathy (i.e. Mad Cow Disease). The prions associated with these diseases are the result of the non-infectious protein taking on an abnormal conformation which serves as a template for the conversion of other like proteins of the cellular (non-prion) conformation to the infectious state [1]. Proteins folding to the prion state cannot only convert non-prion proteins but can also aggregate to form amyloid fibrils. These pathogenic [2] (in mammals) β-sheet-rich fibrils can propagate to notable dimensions and the N-terminal and middle region (NM) of Sup35p, a protein of yeast, has even been used as a template for producing conductive nanowires [3]. Remarkably, amidst the ability of certain proteins to cause incurable disease, prions are thought to play an important role in the development of long-term memory and phenotypic plasticity [4]. Here the latter proposal will be discussed. That is we will look at the role of prions in gene expression. But to understand this we must first briefly review the field of epigenetics.

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Epigenetics

Epigenetics is a term with multiple meanings in biology [5]; however the term here will be used along the lines of the definition first put forth by Conrad Waddington. We make the distinction between genetics and epigenetics as follows: epigenetics relates to heredity and the expression of genes as opposed to the genetic information itself [6] . That is to say that there is the potential for variability of expression without direct alteration of the DNA. As such we are here interested in the phenotype of an entity rather than its genotype. Known epigenetic mechanisms [7] include histone modification via intracellular signaling or as an indirect result of DNA methylation, RNA interference (RNAi), and prion interference which will be the focus of this article. As discussed in reference 7, histones contain N-terminal tails that reach further than the boundary of the chromosome. These tails undergo posttranslational modification which results in the so-called histone code that guides the “transcriptional machinery.” Four known histone modification processes include acetylation, methylation, ubiquitylation and phosphorylation; these processes by altering the chromatin, ultimately serve to control the extent to which genes are expressed.

DNA can be methylated at specific cytosine residues by enzymes known as DNA methyltransferases (DNMTs). Methylation results in structural change in histones and this is known to result in downregulation (i.e. reduced expression) of the effected gene.

RNAi is found to occur in situations in which dsRNA is present and contains sequences homologous to those in mRNA. This results in a change in the degree to which genes are expressed as mRNA degradation is catalyzed before translation occurs [8].

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Role of Prions in Epigenetics

It should be noted that beneficial, or at least non-pathogenic, characteristics of prions are reported for certain proteins of yeast and that analogous roles for mammalian prions have not been discovered. A commonly discussed yeast prion is [PSI +], the abnormal conformation of Sup35p, a protein that regulates translation termination. [PSI +] is said to be a genetic element and be inherited [9]. It can bestow a survival advantage by way of allowing translational read through that Sup35p normally suppresses, giving access to hidden genetic traits. Therefore cells have one-step access to multiple phenotypes via the conversion of a protein to its prion state, and such conversions are reported to occur in response to environmental change [10].

It is also well known that conversion to the prion state may take place as a result of random fluctuation though. Given that in this scenario a reduction in translational fidelity would occur, it is not obvious how cells could tolerate the existence of prions in their native environment; however, as references 4 and 9 point out, prions have survived evolutionary pressure for one hundred million years or more. The ability for the cell to tolerate the prion lies in the rarity of the prion conformation under normal circumstances [9]. So as the example of [PSI +] shows, prions can provide a means of phenotypic diversity and confer the potential to evolve.

Much research has been undertaken to understand the possible beneficence of the [Het-s], [RNQ+] and [URE3] prions but relatively little is understood about these prions at this point. Nonetheless authors are often optimistic that further studies on prions will lead to revelations in the field of epigenetics. Shorter and Lindquist even liken prions to evolutionary capacitors. Loss-of-function mutations are when an expressed gene possesses diminished functionality. It has been shown that such loss-of-function mutations that confer phenotypic plasticity could induce rapid evolution by way of displaying hidden traits. Therefore any prion that mimics such a loss-of-function mutation can be viewed as an instrument of evolution and one that does not require the alteration of the underlying genetic code.

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