Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

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 temperature	Temperature-induced transcriptome changes potentially up to F14 generation	Heat shock reduces H3K9me3 to facilitate de-repression of endogenously repressed repeats (DNA transposons)	Klosin et al[43], 2017	Repetitive elements as etiological factors for schizophrenia (SZ), bipolar disorder and major depression (review)	Darby and Sabunciyan 2014[44]
		No difference in another repressive mark, H3K27me3		Altered 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 unchanged		Tissue-specific repetitive elements expression differences in Parkinson’s disease	Billingsley et al[170], 2019
Heat shock	Maternal 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 investigated	Histone H3 occupancy at hsp70 genes decreased following heat shock	Das et al[9], 2020	MDD associated with increased hsp70 expression in post mortem dorsolateral prefrontal cortex	Martín-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 MDD	Pasquali et al[54], 2018
				Decreased Hsp70 expression in CA4 associated with complete seizure remission for temporal lobe epilepsy	Kandratavicius et al[171], 2014
NA	NA	Transgenerational inheritance of H3K36me3 is regulated by two distinct histone methyltransferases, MES-4 and MET-1	Kreher et al[172], 2018	H3K36me3 implicated in SZ susceptibility SNPs. But histone lysine methyltransferases yet to be investigated in the context of SZ	Niu et al[65], 2019
NA	NA	Lifespan regulated by the H3K9me2 methyltransferase MET-2	Lee 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 genes	Chase et al[50], 2019
				Reduced H3K9me2 at oxytocin and arginine vasopressin gene promotors in a rodent model of stress-induced depression. Rescued by physical exercise	Kim et al[51], 2016
				Cdk-5 targeted H3K9me2 attenuates cocaine-induced locomotor behaviour and conditioned place preference in a rodent model of addiction	Heller et al[52], 2016
NA	Decline in fertility	H3K4me2 demethylase spr-5	Greer et al[173], 2014	Treatment with antipsychotic drug olanzapine increased H3K4me2 binding on gene loci associated with adipogenesis and lipogenesis in a rat model	Su et al[174], 2020
				KDM5C gene that encodes the H3K4me2/3 histone demethylase linked to autism and intellectual disability	Vallianatos et al[175], 2018
Heavy metal (arsenite) stress	Increased resistance to oxidative stress up to F2 generation; no change in reproduction or lifespan	H3K4me3 complex components (wdr-5.1, ash-2, set-2), and transcription factors daf-16 and hsf-1	Kishimoto et al[10], 2017	Increased H3K4me3 associated with three synapsin gene variants in bipolar disorder and major depression	Cruceanu et al[63], 2013
				SZ risk variants are over-represented in association with H3K4me3 in human frontal lobe	Girdhar et al[64], 2018
				H3K4me3 implicated in SZ susceptibility SNPs	Niu et al[65], 2019
				Increased H3K4me3 associated with increased Oxtr gene expression in a rat model of methamphetamine addiction	Aguilar-Valles et al[68], 2014
Hyperosmotic stress	Increased resistance to oxidative stress up to F2 generation	Not further investigated in study	Kishimoto et al[10], 2017	Relevance to human health presently unclear
Larval starvation	Increased resistance to oxidative stress up to F2 generation	Not further investigated in study	Kishimoto et al[10], 2017	Relevance to human health presently unclear
Larval starvation	NA	Thirteen 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 memory	Andolina et al[84], 2016
				miR-34 differentially expressed in induced pluripotent stem cells derived from schizophrenia patients	Zhao et al[176], 2015
				miR-34a regulates expression of p73, a p53-family member, that is implicated in neuronal differentiation	Agostini et al[86], 2011
Starvation	Increased longevity of progeny up to F3 generation	Inheritance of small RNAs through at least 3 generations.	Rechavi et al[11], 2014	miRNAs and rRNAs make up the majority of exRNAs in human plasma	Danielson et al[91], 2017
		Small RNAs regulating expression of genes involved in nutrition, metabolic health and lipid transport		1 specific exRNA predicted diagnosis of Alzheimer’s disease	Yan 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