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February28,2017 Health&Physiology Whathappenstoourgenesinthetwilightofdeath? byPeterNoble1|Professor,AlexPozhitkov2|ResearchScien3st 1:DepartmentofPeriodon3cs,UniversityofWashington,Sea[le,USA 2:DepartmentofOralHealthSciences,UniversityofWashington,Sea[le,USA ThisBreakwaseditedbyCarlosJavierRivera-Rivera,Scien3ficEditor-TheScienceBreaker Death -- the ul3mate end of everyone's journey. What is there to study? Is anything interes3nghappening?Asidefromreligiousand philosophical discourses, valuable knowledge might be obtained from tangible physical facts. Consider an analogy: a disaster happens in a chemical plant that results in its halt and poten3al destruc3on. A chemical plant is a complex chain of reactors linked together by a mul3tude of control networks that normally determine its func3onality. Most disaster-like processes involve a sequence of events that occurs due to the availability of residual energy andmaterials.Understandingthisprocesshelps us determine whether it may be stopped and reverted. It might even provide informa3on on whatpartsaresalvageable.Similartoadisaster atachemicalplant,ourstudyinves3gatedgene expression in postmortem animals in order to project our findings to adult humans that have suddenlydied. Humans are complex creatures capable ofelaboratefunc3ons,suchastheabilitytotalk, walk, and monitor the environment – all at the same 3me. This capacity is due to the coordinated "turning-on" and "turning-off" of thousandsofgenesattheright3me,intheright place, and in the right amount (1). The genes that are "turned-on" (i.e., ac3vated) produce messages (transcripts) that ul3mately enable elaborate func3ons. There is a lack of informa3on about these processes in death, such as when a person suddenly dies from a massive heart a[ack or severe brain injury. Several studies have inves3gated the effects of cell death on gene expression; however, the study of gene expression in death has received TheScienceBreaker|SciencemeetsSociety li[letonoa[en3onsofar. We extracted gene transcripts (i.e. messages from genes which are "turned-on") fromdeadzebrafishandtheliversandbrainsof dead mice that were incubated for 3mes spanning from life to 48-96 h postmortem. At each 3me sample, the abundances of gene transcriptswerepreciselydeterminedbyusinga techniquecalled"GeneMeter"(2,3).Agenewas iden3fied as being ac3vated (i.e., "turned-on") whenitstranscriptsweremoreabundantinthe dead 3ssue than in flash-frozen, i.e., "live" 3ssue. We determined the func3ons of the ac3vated genes by surveying the literature and they were characterized into major categories, ranging from genes involved in embryo development to those involved in detec3ng infec3onorinjury. Hundreds of genes were ac3vated in the twilight of death -- the period of 3me between the cessa3on of elaborate func3ons and the death of all cells. Interes3ngly, the genes were ac3vated reproducibly in several individuals. They were not all ac3vated at the same 3me – nor were they ac3vated at random. Rather, the geneswereac3vatedsequen3ally,sugges3ngan ordertotheac3va3onofgenesindeath.These findingsarerelevanttoforensicsciencebecause the 3ming of the ac3va3ons could be used to precisely determine the 3me of death (i.e., postmortem interval) in suspicious crimes and naturaldeaths(4). As expected, genes involved in survival and in stress response were ac3vated in the twilightofdeath.Productsfromthesegenesare designedtocopewithperturba3onsandtohelp restorehomeostasis. 1of2 What was unexpected was that genes involved in embryo development and cancer were ac3vated. Developmental genes, typically ac3vated during embryonic stages, are usually silenced (for life) following those stages (7). Ac3va3onofthesegenessuggeststhattheyare no longer silenced presumably because either the postmortem physiological condi3ons resemble those during development or simply because “the brakes are burned”. It is possible that the ac3va3on of these genes involves the unwinding of the compacted genomic DNA that in turn allows access to other genes that were previously silenced (e.g., development genes). Theac3va3onofcancer-associatedgeneswasa serendipitous finding, discovered through a survey of cancer databases. Apparently, the number of ac3vated cancer genes increased from minutes aker death to up to 24 h postmortem and then stopped. This has implica3ons to liver transplant recipients because cancer-associated genes may be ac3vated in the donor and transferred to the recipient,resul3nginanincreasedriskofcancer. Apparently, pa3ents with liver transplants have ahigherincidenceofcancerthancontrolgroups (5,6). Liver Transplanta3on: A Popula3on-Based Study", Journal ofHepatology34,no.1(2001):84-91. 7.VladimirB.Teifetal.,"NucleosomeReposi3oningLinks DNA(De)Methyla3onAndDifferen3alCTCFBindingDuring Stem Cell Development", Genome Research 24, no. 8 (2014):1285-1295. ADDITIONALREFERENCES: 1.FrançoisJacobandJacquesMonod,"Gene3cRegulatory Mechanisms In The Synthesis Of Proteins", Journal of MolecularBiology3,no.3(1961):318-356. 2. Alex E. Pozhitkov et al., "A Revised Design For Microarray Experiments To Account For Experimental Noise And Uncertainty Of Probe Response", PLoS ONE 9, no.3(2014):e91295. 3. A. Harrison et al., "Physico-Chemical Founda3ons Underpinning Microarray And Next-Genera3on SequencingExperiments",NucleicAcidsResearch41,no.5 (2013):2779-2796. 4. Pozhitkov A.E. and Noble P.A. 2016. Accurate predic3onsofpostmortemintervalusinglinearregression analyses of gene meter expression data. Accepted February23,2017,ForensicScienceInterna@onal 5.FredrikÅbergetal.,"RiskOfMalignantNeoplasmsAker Liver Transplanta3on: A Popula3on-Based Study", Liver Transplanta@on14,no.10(2008):1428-1436. 6.ElizabethBHaagsmaetal.,"IncreasedCancerRiskAker TheScienceBreaker|SciencemeetsSociety 2of2