The Mechanisms Of Infection Effects Induced Epigenetic Inheritance Of Longevity And Immunity In C.elegans

Adverse environment in early life can alter the phenotypic plasticity and influence the health in adult and offspring.The impact of phenotypic variation that induced by early life environment has been demonstrated to last multiple generations in humans,animal models and plants.After two decades,great strides have been made in indentifying the mechanisms of inter/transgenerational phenotype transmission that include RNA methylation,DNA methylation,histone modification,and noncoding RNA transcripts.For example,DNA methylationcorrelates withmacronutrient and early life stress induced inter/transgenerational phenotypes.Recent studies showed that RNA also has been implicated in phenotype transmission.Small noncoding RNA is closely linked to starvation and heat-shock-induced epigenetic memory.Furthermore,in model organism C.elegans and Drosophila,chromatin organization and histone modification have been reported to elicit inter/transgenerational memorytransmission.Although these advances,however,the epigenetic mechanism responsible for transgenerational inheritance of infection induced aging remains unknown.We present a C.elegans model of infection induced epigenetic inheritance and identify genes responsible for its encoding in progeny.The main findings were described as follows:1.Infection during developmental stages induced the lifespan reduction and the immunity enhanced in adulthood and revealed a trade-off effect.Furthermore,we found that F1 descendants from infectedP0 parents exhibited reduced lifespan and enhanced immunity compared with those worms from control parents.Interestingly,F2 and F3 descendants from infected parental generation also showed decreased lifespan and increased immunity compared with those animals from control parents.However,despite the F4 descendants from infectedand uninfected parental generation have no significant differences in lifespan and immunity.Thus,the infection of the parental generation induced the lifespan reduction and immunity enhance of subsequent generations.2.Either the paternal or the maternal effects of infection could be transmitted across three consecutive generations.3.Histone modification was derived from the infected P0 generation and the histone H3K4me3 complex is responsible for the transmission of infection effects through the three consecutive generations.The histone H3K4me3 complex enhanced innate immunity in C.elegans.4.Acomplished the tissue-specific geneknockdown experiments by usingNL2098 strains in germline,TU3401 strains in neuron,MGH170 strains in intestine,NR222 strains in epidermis,,and NR350 strains in muscle suggested that histone H3K4me3 complex functioned in the germline to regulate epigenetic memory of infection effects across the three consecutive generations.5.Small siRNAs induced by infection are inherited throughthree consecutive generations.22 G siRNAs are the most abundant differentially expressedsmall RNAs that are carried by the argonaute proteins CSR-1.The H3K4me3 histone modifiers act in germline through CSR-1 bound 22G-siRNAs to regulate transgenerational inheritance of infection effects.GO analysis has revealed that an array of gene targets ofthe transgenerationally inherited small RNAs cluster in regulation of aging and immune response.6.We map a mechanism that orchestrates parental infection and the H3K4me3 histone modifiers and it regulates small RNAs target genes directlyto phenotypic output of the descendants.Our findings provide an evidence of transgenerational inheritance of infection effects and insights into our understanding of diversity phenotypic outcomes and evolution.