Cellular memory of stressful situations28 January 2015

Marc Bhler and his group at the Friedrich MiescherInstitute for Biomedical Research (FMI) have identified acellular mechanism that buffers stress-induceddisruption of heterochromatin and the toxic aggregationof a prion protein. If this mechanism malfunctions,changes in the epigenome remain and are thusremembered for many cell divisions, long after thestressful situation resolved.

Stress is unhealthy. The cells use therefore avariety of mechanisms to deal with stress and avertits immediate threat. However, certain stressfulsituations leave marks that go beyond theimmediate response; some even seem to bepassed on to the next generation. One school ofthought that has gained a lot of attention lately,hypothesizes that the epigenome, chemicalmodifications on the DNA and on proteins, carriesinformation about external influences such asstress. However, when and how environmentalcues trigger changes in the epigenome and thusinfluence our response has remained largelyunknown.

To investigate how the environment can influenceepigenetic processes, FMI Senior group leaderMarc Bhler and his group work with fission yeast.In a paper published in Cell Reports, they reportthe identification of a regulatory circuit that buffers

a potentially deleterious epigenetic switch understressful conditions. The capacity to prevent suchan epigenetic change is important to the organism,perhaps because the altered epigenetic state ismaintained for many cell divisions, well after thestress has subsided.

Unicellular organisms such as fission yeast can beeasily stressed with high temperatures, which arecommonly encountered in the wild. One highlyconserved protein that is particularly sensitive tohigh temperatures is Dicer. Under normalcircumstances, it sits in the nucleus andamongother thingsinhibits the expression of genes thatdeal with stress responses. If fission yeast isexposed to high temperatures, Dicer leaves thenucleus and accumulates in the cytoplasm. Thisallows expression of the stress response genes.Thus, by moving out of the nucleus, Dicer enablesfull activation of the yeast's stress response.

In their study, Bhler and colleagues usedcorrelative light and electron microscopy (CLEM) toshow that Dicer accumulates as an aggregate in anovel cytoplasmic compartment during heat stress.There, Dicer is joined by the well-known proteindisaggregase Hsp104, which dissolves the Diceraggregates. Dicer then recycles back to thenucleus. "What is particularly intriguing is thatHsp104 is one of the "stress genes" that isrepressed by Dicer in the nucleus. Hsp104 thusguarantees that Dicer can again take on its nuclearfunctions, one of them being the repression of"stress genes" like HSP104. Thus we are dealing awith classical negative feedback loop", explainsBhler.Which brings us to the other highly relevantfunction of Dicer in this context: Dicer ensures thestability of the yeast genome by maintaining thedense packaging of the centromeric regions intoheterochromatin. Without heterochromatin,chromosomes segregate improperly during mitosis.This can result in aneuploidy and chromosomeinstability, which are a hallmark of cancer. In their

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paper, the FMI scientists show that in the absenceof Hsp104, Dicer remains in the cytoplasm andheterochromatic regions on the yeast genome areno longer stable after exposure to heat stress. Thisleads to changes in gene expression and mostdeleteriously, chromosome missegregation duringcell division. "The observed changes inheterochromatin and gene expression incurredafter a stressful situation in the absence offunctional Hsp104, are still present long after thestress has subsided," comments Bhler. "What wehave here is a phenomenon that complies with theclassic definition of epigenetics: an event where anenvironmental cue triggers a change in geneexpression that does not entail a change in thegenomic sequence, yet which is inherited for manycell divisions, even after the environmental cue hasdisappeared."

In an interesting twist, Bhler and his team alsoshowed that the feedback loop that controls Dicerand Hsp104, plays a role during prion formationand propagation. In other organisms, Hsp104 waswell-knownfor its function in the aggregation ofprionogenic proteins. Indeed, the FMI scientistsfound that without Dicer, Hsp104 is off its leash andincreases the frequency of toxic prionogenic proteinaggregates that eventually lead to cell death."Given that protein aggregates play an importantrole not only in prion diseases but also inneurodegenerative disorders, the processesdescribed in yeast may become an interestingavenue for future studies into diseases likeAlzheimers," comments Bhler.

At the frontier of microscopy: Correlative Lightand Electron Microscopy (CLEM) & Serial BlockFace Scanning Electron Microscopy (SBFEM)

SBFEM allows the three dimensionalreconstruction of the structures within a celland tissues at a high resolution (see pictureof the cell). An ultramicrotome integratedwithin the specimen chamber of a scanningelectron microscope cuts away a thin sliceof the specimen, only 50-100 nanometersthick, thus allowing the instrument to scanthe next "layer". Sequential 2D images are

then assembled to a 3D image of the celland its structures. For their project, thescientists profited substantially from in-house expertise at the Facility for AdvancedImaging and Microscopy (FAIM), namelyChristel Genoud, who is a leading expert inSBFEM.CLEM is a highly sophisticated microscopymethod that is mastered by only fewlaboratories around the world. It combinesfluorescent light microscopy with electronmicroscopy, two platforms that are normallyseparated. It thus takes advantage of bothtechnologies: light microscopy allows thestudy of processes in whole, often living,cells for example with fluorescent labels.Electron microscopy shows ultrastructuraldetail in parts of cells at a very highresolution. CLEM combines the advantagesof both thus adding detail and providingcomplementary information. An ERCStarting Grant made the introduction ofCLEM at the FMI possible.

More information: Oberti D, Biasini A,Kirschmann MA, Genoud C, Stunnenberg R,Shimada Y, Bhler M (2014) "Dicer and hsp104function in a negative feedback loop to conferrobustness to environmental stress." Cell Rep.2015 Jan 6;10(1):47-61. DOI:10.1016/j.celrep.2014.12.006. Epub 2014 Dec 24.

Provided by Friedrich Miescher Institute forBiomedical Research

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http://dx.doi.org/10.1016/j.celrep.2014.12.006http://dx.doi.org/10.1016/j.celrep.2014.12.006

APA citation: Cellular memory of stressful situations (2015, January 28) retrieved 12 March 2015 from http://phys.org/news/2015-01-cellular-memory-stressful-situations.html

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