Highlights d [ESI + ] is a prion conformer of the Set3C histone deacetylase scaffold Snt1 d [ESI + ] heritably activates transcription at otherwise repressed loci d Activated loci are enriched for sub-telomeres via interference with Rap1 by [ESI + ] d Sub-telomeric expression generates an adaptive transcriptional state

To survive, organisms must orchestrate many competing biochemical and regulatory processes in time and space. Recent work has suggested that the underlying chemical properties of some biomolecules allow them to self-organize, and that life may have exploited this property to organize biochemistry in space and time within cells. Such phase separation is ubiquitous, particularly among the many regulatory proteins that harbor prion-like intrinsically disordered domains. And yet, despite evident regulation by post-translational modification and myriad other stimuli, the biological significance of many phase-separated compartments remains uncertain. Many potential functions have been proposed but far fewer have been demonstrated. A burgeoning subfield at the intersection of cell biology and polymer physics has defined the biophysical underpinnings that govern the genesis and stability of these particles. The picture is complex: many assemblies are composed of multiple proteins that each have the capacity to phase separate. Here, we briefly discuss this foundational work and survey recent efforts combining targeted biochemical perturbations and quantitative modeling to specifically address the diverse roles that phase separation processes may play in biology.

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Epigenetic mechanisms mediate diverse gene expression programs in growth and development. Here we report a protein-based epigenetic element, a prion, formed by the conserved DNA helicase Mph1/FANCM. [MIX+] is a cytoplasmically inherited state with propagation driven by the non-amyloid prion templating of Mph1. [MIX+] provides resistance to DNA damage, a gain-of-function trait that requires helicase activity. [MIX+] reduces mitotic mutation rates, but promotes meiotic crossovers, driving measurable phenotypic diversification in wild outcrosses. Remarkably, [MIX+] can be induced by DNA-damaging stresses in which it is beneficial. Thus, [MIX+] fuels a quasi-Lamarckian form of inheritance that promotes survival of the current generation and diversification of the next.