Epigenetic effects can be mediated by changes in chromatin state that are transmitted from parent to child via gametes, but support is gathering for maternal yolk, which is deposited into ooctyes, as an extranuclear epigenetic factor that can contribute to phenotypic plasticity across generations in Caenorhabditis elegans

Ahmed, S.

Dowen, R.H.

Carolina Digital Repository

Maternal Inheritance: Longevity Programs NourishProgeny via YolkRobert H. Dowen1,2,3,* and Shawn Ahmed3,4,5,*1Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA2Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA3Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA4Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA5Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA*Correspondence: dowen@email.unc.edu (R.H.D.), shawn@med.unc.edu (S.A.)https://doi.org/10.1016/j.cub.2019.06.050Epigenetic effects can be mediated by changes in chromatin state that are transmitted from parent tochild via gametes, but support is gathering for maternal yolk, which is deposited into ooctyes, as anextranuclear epigenetic factor that can contribute to phenotypic plasticity across generations inCaenorhabditis elegans.The possibility that environmental factors,such as diet or stress, might induce anorganism to modify its gametes togenerate progeny with improved fitnesswas initially proposed by Jean-BaptisteLamarck [1]. Such views werearguably heretical before the dawn ofthe 21st century, but factors such ascuriosity, serendipity and thedescription of a variety of ways tomodify metazoan gene expression ina manner that is both heritable andreversible have created significantinterest in the topic of epigeneticinheritance.Normal growthprogramLongevityprogramsElevatedyolkNormal germlinedevelopmentCurrent BiologyAbnormal germline developmentIntergenerational/Uniparental inheritanceStress/small RNAsTransgenerationalinheritanceL1StarvationMaternal provisioningMaternal mitochondriainheritancePaternal tRNAinheritanceL1StarvationDCA BF1F2F3OocyteFertilizationStressMitochondriatransmitted byoocytestRNAhalvesTestisFertilizationEmbryoEmbryoEpididymisF4OocyteHistone modificationssmall RNAsDNA methylationNon-coding RNAstransmitted byspermNormal yolkP0Figure 1. Mechanisms of epigenetic inheritance.(A) Transgenerational inheritance in response to stress or exogenous small RNAs can induce transient multigenerational phenotypes (red). For uniparentalinheritance, cytoplasmic epigenetic factors include (B) tRNA halves in sperm and (C) mitochondria of oocytes. (D) Jordan et al. show that longevity programsmodify yolk abundance in oocytes to license normal development of starved L1 larvae.Transgenerational epigeneticinheritance refers to phenotypes that aretransmitted by female gametes for at leastthree generations (F1, F2 and F3), or bymale gametes for at least two generations(F1 and F2). This excludes the possibilitythat environmental stresses that triggerepigenetic inheritance in F0 animals mightdirectly affect F0 sperm, F0 oocytes oreven F1 fetal oocytes in utero [2]. Maternalor paternal effects that persist across asingle generation are considered aspecialized form of epigenetic inheritancethat is relatively simple to study, termeduniparental or intergenerationalinheritance [3,4]. Maternal provisioning isa form of uniparental inheritance that isdictated by factors that are transmitted tozygotes via oocytes. Altered levels ofgenomic silencing are now recognized asa major molecular driver of epigeneticinheritance [5]. In a recent issue ofCurrentBiology, Jordan et al. discuss a novelmechanism for non-genetic inheritance inCaenorhabditis elegans where theabundance of maternally provisioned yolkcontributes to the developmental successof progeny (Figure 1) [6].Epigenetics refers to a heritable changethat occurs in the absence of genomicDNA mutations. Studies of gene silencinghave revealed roles for histonemodifications, sometimes directed bysmall RNAs, as well as DNA methylationas factors that can control transcription atspecific genomic loci, which, whenestablished in gametes, can betransmitted to offspring [4] (Figure 1A).Other factors that might alter phenotypesvia epigenetic inheritance includemetabolites, proteins, lipids or RNAs. Forexample, paternal diet can influence theabundance of somatically derivedfragments of specific tRNAs, termedtRNA halves, that are secreted from themouse epididymis in vesicles anddeposited into developing spermatozoawhere they impart a form of epigeneticinheritance that is distinct frommodification of DNA or chromatin [7](Figure 1B). Given their size relative tosperm, oocytes could harbor significantnon-nuclear ‘maternal epigenetic factors’such as mitochondria that could alterphenotypic plasticity in offspring [2](Figure 1C).The paper by Jordan et al.demonstrates that induction ofindependent pro-longevity pathways(e.g., dietary restriction or reduced insulin/IGF-1 signaling) in mothers but not fathersalters the developmental success ofprogeny that are confronted with stressfulconditions [6]. C. elegans embryos hatchto become first stage larvae (L1) that willarrest development in the absence offood and can survive for weeks whilesearching for a food source. Extendedperiods of starvation-induced L1 arrestfollowed by reintroduction of food resultsin abnormal germline development. Theauthors discovered that activation oflongevity and stress response pathwaysin somatic cells of mothers generatesoffspring that are better equipped torecover from L1 arrest and developnormally. Moreover, the molecularregulators of longevity that were active inmothers were utilized by their progeny topromote developmental fidelity [6].To gain mechanistic insight into howmodified longevity programs can betransmitted across generations, theauthors investigated whether yolk, whichwas recently implicated in maternalinheritance [8], played a role. Yolk issynthesized in the adult maternal intestineand is composed of vitellogeninlipoproteins and large quantities of lipids.Delivery of these particles to oocytes, aprocess called vitellogenesis, providesembryos with the nutrients they need todevelop until hatching, when the animalsnormally obtain food from theirenvironment. Starvation-induced arrest ofL1 larvae demands that yolk provideadditional resources for survival that arenormally used to propel development.Consequently, mutants defective invitellogenesis have been previouslyshown to survive for shorter periods oftime in L1 arrest [9]. At the same time,reduced yolk production promotessomatic longevity of mothers, possibly byaltering intestinal autophagy pathwaysand/or by activating pro-longevitytranscription factors [10–14]. The authorsused a variety of approaches to showthat deposition of yolk into maternaloocytes may protect starved L1animals from developmental defects(Figure 1D) [6].Jordan et al. expand upon existingmodels of the relationship between yolk,development and longevity by describinga sophisticated mechanism by which anorganism can improve viability acrossgenerations during challenging survivalconditions. In this scenario, longevitysignaling networks interface withvitellogenesis pathways in the mother topromote developmental fidelity in starvedprogeny. One maternal longevity pathwaythat promotes germline development instarved progeny is activated in responseto mutation of the insulin/IGF-1 receptordaf-2, which reduces insulin/IGF-1signaling [6]. Although reductions inDAF-2 signaling have previously beenreported to down-regulate maternalvitellogenin gene expression [12,15,16],yolk deposition in daf-2 mutants couldultimately be elevated due to a dramaticreduction in ovulation rate [17], whichwould increase the amount of time thatoocytes spend receiving yolk deposits.Jordan et al. suggest that vitellogenesiscould serve as an elegant epigeneticstrategy to relay information acrossgenerations [6], and future work mayresolve how longevity pathways altervitellogenin expression and yolk uptake tonourish the next generation.If increased yolk provisioning promotesresistance of L1 larvae to starvation,then this has several ramifications forthe field of transgenerational inheritance.Yolk has the potential to deliver a suiteof bioactive lipids to progeny thatcould be the epigenetic cargo thatreprograms insulin receptor expressionor that modifies the activity of pro-longevity transcription factors in thesubsequent generation [14]. Alternativelysmall RNAs can be transported anddelivered to recipient cells by high-density lipoproteins in mammalianplasma [18,19], so yolk-associatedsmall RNAs could act in the nuclei orcytoplasm during development to modifygene expression or mRNA stability/translation. Thus, if the transgenerationalinheritance described by Jordan et al. isdue to small RNA-dependenttranscriptional regulation in progeny,then this outcome would mirror knownconsequences of nuclear epigeneticinheritance [3].In mammals, pronuclear transferexperiments can be performed toexplicitly test if an epigenetic effect iscaused by oocyte cytoplasm, but suchexperiments are not possible forC. elegans embryos that are encased inrigid eggshells. If cytoplasmic yolk is notsolely responsible for improveddevelopment of starved L1 larvae, then itis possible that other oocyte constituentssuch as hormones, steroids, amino acids,vitamins or even altered chromatin statesin oocyte nuclei might be responsible.Precedent for the daf-2 insulin/IGFreceptor locus being under epigeneticcontrol exists in metazoans, as parent-of-origin-mediated gene silencing affectsmouse development via the insulin/IGF2gene on chromosome 7 as well as theinsulin/IGF2 receptor gene onchromosome 17, both of which arelocated within imprinted loci that areexpressed from the allele that comes fromsperm or oocytes, respectively [20]. If thiswere the case inC. elegans, then the daf-2locus might be silenced in sperm, suchthat crosses of wild-type males with daf-2mutants might result in skewed ormonoallelic expression of the maternal(mutant) daf-2 allele in progeny. Thismight be consistent with the observationthat daf-2 mRNA levels are reduced inprogeny of long-lived mothers [6],although additional genomic loci mightcontribute to recovery of starved L1larvae.In summary, the study by Jordan et al.indicates that longevity pathways modifyoocytes in a manner that confersresistance to starvation-induceddevelopmental defects in their progeny,possibly via a novel epigeneticmechanism that depends on the quality orquantity of yolk in oocytes. Thisfeed-forward uniparental circuitoffers an unexpected twist to thespecial relationship between motherand child.REFERENCES1. Kovac, L. (2019). Lamarck and Darwinrevisited. EMBO Rep. 20, e47922.2. Heard, E., and Martienssen, R.A. (2014).Transgenerational epigenetic inheritance:myths and mechanisms. Cell 157, 95–109.3. Perez, M.F., and Lehner, B. (2019).Intergenerational and transgenerationalepigenetic inheritance in animals. Nat. CellBiol. 21, 143–151.4. Rando, O.J. (2012). 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Maternal Inheritance: Longevity Programs Nourish Progeny via Yolk

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Maternal Inheritance: Longevity Programs Nourish Progeny via Yolk

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