Review
Copyright ©The Author(s) 2021.
World J Psychiatr. Oct 19, 2021; 11(10): 711-735
Published online Oct 19, 2021. doi: 10.5498/wjp.v11.i10.711
Table 1 Studies of transgenerational epigenetic inheritance in Caenorhabditis elegans of relevance to neuropsychiatric conditions and mammalian preclinical models
Type of stress (if applicable to study)
Transgenerational shifts in progeny phenotypes
Epigenetic modifications implicated in the inheritance process
Ref.
Psychiatric conditions with similar epigenetic pathology
Ref.
Elevated temperatureTemperature-induced transcriptome changes potentially up to F14 generationHeat shock reduces H3K9me3 to facilitate de-repression of endogenously repressed repeats (DNA transposons)Klosin et al[43], 2017Repetitive elements as etiological factors for schizophrenia (SZ), bipolar disorder and major depression (review)Darby and Sabunciyan 2014[44]
No difference in another repressive mark, H3K27me3Altered expression of human endogenous retroviruses associated with autism spectrum disorder and SZ (review)Misiak et al[169], 2019
Active histone marks H3K36me3 and H3K4me2 both unchangedTissue-specific repetitive elements expression differences in Parkinson’s diseaseBillingsley et al[170], 2019
Heat shockMaternal heat shock altered survival of F1 progeny through 5-HT dependent HSF-1 recruitment to heat shock protein gene promotors. Persistence of phenotypic changes not investigatedHistone H3 occupancy at hsp70 genes decreased following heat shockDas et al[9], 2020 MDD associated with increased hsp70 expression in post mortem dorsolateral prefrontal cortexMartín-Hernández et al[53], 2018
Elevated serum HSP70 levels predicted development of MDD for premenopausal women. Serum HSP70 decreased over time for women who did not develop MDDPasquali et al[54], 2018
Decreased Hsp70 expression in CA4 associated with complete seizure remission for temporal lobe epilepsyKandratavicius et al[171], 2014
NANATransgenerational inheritance of H3K36me3 is regulated by two distinct histone methyltransferases, MES-4 and MET-1Kreher et al[172], 2018 H3K36me3 implicated in SZ susceptibility SNPs. But histone lysine methyltransferases yet to be investigated in the context of SZNiu et al[65], 2019
NANALifespan regulated by the H3K9me2 methyltransferase MET-2Lee et al[49], 2019 H3K9me2 elevated in post-mortem SZ brains and peripheral blood cells. Treatment with histone methyltransferase inhibitor BIX-01294 decreased H3K9me2 levels and rescued expression of SZ risk genesChase et al[50], 2019
Reduced H3K9me2 at oxytocin and arginine vasopressin gene promotors in a rodent model of stress-induced depression. Rescued by physical exerciseKim et al[51], 2016
Cdk-5 targeted H3K9me2 attenuates cocaine-induced locomotor behaviour and conditioned place preference in a rodent model of addictionHeller et al[52], 2016
NADecline in fertilityH3K4me2 demethylase spr-5Greer et al[173], 2014 Treatment with antipsychotic drug olanzapine increased H3K4me2 binding on gene loci associated with adipogenesis and lipogenesis in a rat modelSu et al[174], 2020
KDM5C gene that encodes the H3K4me2/3 histone demethylase linked to autism and intellectual disabilityVallianatos et al[175], 2018
Heavy metal (arsenite) stressIncreased resistance to oxidative stress up to F2 generation; no change in reproduction or lifespanH3K4me3 complex components (wdr-5.1, ash-2, set-2), and transcription factors daf-16 and hsf-1Kishimoto et al[10], 2017 Increased H3K4me3 associated with three synapsin gene variants in bipolar disorder and major depressionCruceanu et al[63], 2013
SZ risk variants are over-represented in association with H3K4me3 in human frontal lobeGirdhar et al[64], 2018
H3K4me3 implicated in SZ susceptibility SNPsNiu et al[65], 2019
Increased H3K4me3 associated with increased Oxtr gene expression in a rat model of methamphetamine addictionAguilar-Valles et al[68], 2014
Hyperosmotic stressIncreased resistance to oxidative stress up to F2 generationNot further investigated in studyKishimoto et al[10], 2017Relevance to human health presently unclear
Larval starvationIncreased resistance to oxidative stress up to F2 generationNot further investigated in studyKishimoto et al[10], 2017Relevance to human health presently unclear
Larval starvationNAThirteen miRNAs up-regulated (miR-34-3p, the family of miR-35-3p to miR-41-3p, miR-39-5p, miR-41-5p, miR-240-5p, miR-246-3p and miR-4813-5p); Two miRNAs down-regulated (let-7-3p, miR-85-5p)Garcia-Segura et al[77], 2015 Eight differentially expressed blood miRNAs linked to PTSD. Four up-regulated (miR-19a-3p, miR-101-3p, miR-20a-5p, miR-20b-5p). Four down-regulated (miR-486-3p, miR-125b-5p, miR-128-3p, miR-15b-3p)Martin et al[78], 2017
Deletion of miR-34 family in mice facilitates resilience to stress-induced anxiety and extinction of fear memoryAndolina et al[84], 2016
miR-34 differentially expressed in induced pluripotent stem cells derived from schizophrenia patientsZhao et al[176], 2015
miR-34a regulates expression of p73, a p53-family member, that is implicated in neuronal differentiationAgostini et al[86], 2011
StarvationIncreased longevity of progeny up to F3 generationInheritance of small RNAs through at least 3 generations. Rechavi et al[11], 2014 miRNAs and rRNAs make up the majority of exRNAs in human plasmaDanielson et al[91], 2017
Small RNAs regulating expression of genes involved in nutrition, metabolic health and lipid transport1 specific exRNA predicted diagnosis of Alzheimer’s diseaseYan et al[94], 2020
exRNAs are potentially involved in the paternal intergenerational influence on offspring metabolic health (mouse model)van Steenwyk et al[93], 2020