A Prion Epigenetic Switch Establishes an Active Chromatin State

Harvey, Zachary H.; Chakravarty, Anupam K.; Futia, Raymond A.; Jarosz, Daniel F.

doi:10.1016/j.cell.2020.02.014

Cited by 61 publications

(50 citation statements)

References 112 publications

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“…Transient overexpression of yeast prion proteins induces the proteins to form aggregates that are self-seeding and efficiently fragment, so they propagate even after overexpression is removed ( Alberti et al., 2009 ; Byers and Jarosz, 2017 ; Chakrabortee et al., 2016 ; Chakravarty et al., 2020 ; Derkatch et al., 1996 ; Du et al., 2008 ; Harvey et al., 2020 ; Itakura et al., 2020 ; Liebman and Chernoff, 2012 ; Patel et al., 2009 ; Wickner, 1994 ). Thus, transient overexpression of mutant or wild-type p53 could increase the likelihood of de novo p53 prion formation and inactivation, leading to a chain reaction of p53 aggregation and aggregate replication.…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets

Park

Pentek

et al. 2021

iScience

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Section: Introductionmentioning

confidence: 99%

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets

Park

Pentek

et al. 2021

iScience

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“…This suggests that the epigenetically inherited reproductive defects documented in the descendants of mutants that lack AMPK signalling very likely re ect the extreme effects of starvation on the germ line, although they occur after a much shorter delay in these mutants. This transgenerational epigenetic inheritance has been observed in several contexts in C. elegans and the progressive mortalization of the germ line is often associated with aberrant changes in the histone modi cations typically present in the affected germ cells [7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

Sun¹,

Sherrin²,

Roy³

2021

Preprint

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During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

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“…For example, Saccharomyces cerevisiae employs the [GAR + ] prion to switch between specialist and generalist carbon-source utilization strategies, a switch that is heritable (26,27). The [ESI + ] prion drives the emergence and transgenerational inheritance of an activated chromatin state that can result in broad resistance to environmental stress, including antifungal drugs (28). The [SMAUG + ] prion allows yeast to anticipate nutrient repletion after periods of starvation, providing a strong selective advantage (17).…”

Section: Introductionmentioning

confidence: 99%

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

Zajkowski

Lee

Mondal

et al. 2020

Preprint

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Prions are proteins capable of acquiring an alternate conformation that can then induce additional copies to adopt this same alternate conformation. Although initially discovered in relation to mammalian disease, subsequent studies have revealed the presence of prions in Bacteria and Viruses, suggesting an ancient evolutionary origin. Here we explore whether prions exist in Archaea - the last domain of life left unexplored with regard to prions. After searching for potential prion-forming protein sequences computationally, we tested candidates in vitro and in organisms from the two other domains of life: Escherichia coli and Saccharomyces cerevisiae. Out of the 16 candidate prion-forming domains tested, 8 bound to amyloid-specific dye, and six acted as protein-based elements of information transfer, driving non-Mendelian patterns of inheritance. We additionally identified short peptides from archaeal prion candidates that can form amyloid fibrils independently. Candidates that tested positively in our assays had significantly higher tyrosine and phenylalanine content than candidates that tested negatively, suggesting that the presence of these amino acids may help distinguish functional prion domains from nonfunctional ones. Our data establish the presence of amyloid-forming prion-like domains in Archaea. Their discovery in all three domains of life further suggests the possibility that they were present at the time of the last universal common ancestor (LUCA).Significance StatementThis work establishes that amyloid-forming, prion-like domains exist in Archaea and are capable of vertically transmitting their prion phenotype – allowing them to function as protein-based elements of inheritance. These observations, coupled with prior discoveries in Eukarya and Bacteria, suggest that prion-based self-assembly was likely present in life’s last universal common ancestor (LUCA), and therefore may be one of the most ancient epigenetic mechanisms.

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A Prion Epigenetic Switch Establishes an Active Chromatin State

Cited by 61 publications

References 112 publications

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

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