Mapping Out Histone Post‐Translational Modifications in a Yeast Prion Model

Prions are proteins with the ability to self‐template into alternative folds, allowing them to operate outside the canonical steps of the central dogma of molecular biology. Interestingly, while these infectious protein species are responsible for causing several diseases in humans and animals alike, they have also been postulated to provide positive cellular outcomes in yeast. Because of proteins propensity to misfold and aggregate, prions could allow for environmental adaptiveness without directly affecting an organism’s genome. However, the exact mechanisms by which these proteins could potentially lead to gene utilization changes are not known, and the extent of their roles in normal cellular biology has not been adequately investigated. Rnq1 and Swi1 are two such yeast prion proteins, each responsible for the propagation of the [PIN+] and [SWI+] prion states, respectively. Due to the ease with which prion states exchange, we hypothesize that they could be connected to particular changes in histone post‐translational modifications (PTMs) to alter the way that genes are expressed, and thus could be the key to understanding how prions impact cellular phenotypes. Through previously published methods, we have begun to map out the changes in histone PTM levels between yeast prion states. Overall, [PIN+] yeast showed increased levels of H3K9ac, H3K18ac, and H3K56ac compared to [pin‐]. Interestingly, all these modifications are correlated with increased gene transcription. In agreement, we find higher levels of total RNA in [PIN] yeast. Furthermore, [SWI+] yeast have shown a decrease in H3K56ac and H3K36me2 levels compared to [swi‐] cells. Decreases in these marks generally represent decreased gene expression, which agree with the decrease in global RNA levels in [SWI+] compared to [swi‐] samples. Furthermore, treatment with 1mM guanidinium hydrochloride (GuHCl) ‐ to shut off or “cure” the prion state in yeast‐ reversed the observed histone PTM level changes. Here, we have effectively shown that the yeast epigenome is directly linked to prion states, further confirming the role of prions as another form of epigenetic modulation.