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

Table 2 Studies of transgenerational epigenetic inheritance in Drosophila melanogaster of potential relevance to psychiatric conditions and mammalian preclinical models

Type of stress (if applicable to study)	Transgenerational shifts in progeny phenotypes	Epigenetic processes implicated in the inheritance process	Ref.	Potentially relevant psychiatric conditions	Ref.
Thermal stress (selection based on intolerance to heat stress)	Reduced ability to fly by F2 generation, maintain through to F4 generation	Epigenetic mechanism not investigated; aspects of stress physiology that affect flight still unclear	Krebs and Thompson[111], 2006	Relevance to human health presently unclear.
Mild heat stress(embryos maintained at 29 °C)	De-suppression of white gene up to F4 generation	Disruption of polycomb group (PcG) protein complex affecting H3K27me3	Bantignies et al[114], 2003	Despite multiple reports of altered H3K27me3, the involvement of PcG protein complexes in human psychopathologies has not been established
Heat shock (flies exposed to 37 °C for 1 h)	De-suppression of white gene sustained up to F3 generation required repeated exposure to the same paternal stressor. Gradual return to normal upon removal of heat shock	Disruption of pATF-2 mediated heterochromatin assembly	Seong et al[121], 2011	Rat model of chronic stress reported increased ATF-2 gene expression in the frontal cortex of chronically stressed rats, which is decreased following chronic antidepressant treatment	Laifenfeld et al[122], 2004
				pATF-2 levels are increased in post mortem samples of unmedicated vs medicated patients with MDD. No differences detected for bipolar disorder or schizophrenia	Gourzis et al[177], 2012
				Case report of decreased chromosome 1 heterochromatin in FTLD, misdiagnosed as SZ. Altered size distribution of chromosome 1 heterochromatic region in unrelated SZ patients compared to controls	Kosower et al[178], 1995
				Risperidone inhibition of heterochromatin formation in human liposarcoma cells in vitro, in a process involving PKA signalling; extent of dysregulated heterochromatin in psychosis yet to be explored	Feiner et al[125], 2019
				Parental exposure to risperidone led to intergenerational effects on F1 predator avoidance behaviours in zebrafish; potential human effects have not been investigated	Kalichak et al[179], 2019
Heat stress (flies raised at 29 °C)	Suppression of BX2 transgene cluster over multiple (50) generations	Paramutation of BX2 via maternally inherited piRNAs, triggered by heat stress which resulted in active transcription of piRNAs within that gene locus	de Vanssay et al[126], 2012	Paramutation is not regarded as an established epigenetic process in mammals
				However, readers should be aware of this proof-of-concept study in mice	Yuan et al[180], 2015
			Casier et al[127], 2019	Paternal transmission of “white-tail-tip” phenotype caused by paramutant allele in mice limited to one generation. Maternal miRNAs and piRNAs regulate (inhibit) germline transmission of paramutation
				14 piRNAs differentially expressed in AD prefrontal cortex samples vs controls	Qiu et al[128], 2017
				Sequencing of CSF-derived exosome sncRNA revealed combination of 3 miRNAs and 3 piRNAs detected AD and predicted the conversion of mild–cognitive impaired (MCI) patients to AD dementia. Greater predictive confidence when combining the smallRNA signature with pTau and Aβ 42/40 ratio pathology	Jain et al[129], 2019
Forced cohabitation with predator or endoparasitoid wasps	Stressed females shift behaviour to laying eggs on food rich in ethanol, and that preference is inherited through five generations	Maternal inheritance of chromosome III and NPF (Drosophila homolog of NPY) gene locus, reduced NPF expression in the fan shaped body of the adult brain drives ethanol preference	Bozler et al[136], 2019	Dysregulation of NPY levels in the brain is a key pathophysiology of drug addiction. Manipulation of NPY neurotransmission has potentially beneficial behavioural outcomes, depending on the drug in question	Gonçalves et al[181], 2016
				NPY is implicated in human alcohol misuse disorders	Mayfield et al[137], 2002
				NPY is also implicated in rodent models of alcohol misuse disorder	Mottagui-Tabar et al[138], 2005
					Thorsell and Mathe[139], 2017
					Badia-Elder et al[140], 2003
					Schroeder et al[142], 2005
					Robinson et al[141], 2019
Restraint stress	Paternal restraint stress affects epigenome, transcriptome and metabolome of F1 progeny	Stress-induced up-regulation of Upd3 (Drosophila homolog of IL-6) in somatic cells and testes, activating JAK/STAT pathway	Seong et al[145], 2020	Metabolic dysregulation in the F1 offspring derived from male breeders exposed to early postnatal stress	van Steenwyk et al[146], 2018; van Steenwyk et al[93], 2020
		Subsequent p38 activation results in dATF-2 deactivation in germ cells leading to decreased H3K9me2 (repressive mark) at target genes. Repressive histone marks inherited by F1 progeny		Review of epigenetic mechanisms proposed to underlie intergenerational transmission of paternal trauma	Yehuda and Lehrner[182], 2018
				Childhood adversity associated with altered DNA methylation of HPA axis and immune system genes; potentially inherited by offspring	Bick et al[154], 2012
Methylphenidate (MPH) treatment	Behavioural response to MPH is genetically variable and intergenerational effects can be observed in F1 offspring	Mechanism is unknown but MPH resulted in alterations to expression of many histone modifying genes	Rohde et al[158], 2019	ADHD is highly heritable, but the reasons are unclear despite the identification of candidate genes. Future studies should attempt to identify transgenerationally heritable epigenetic modifications as the basis for genetic vulnerability
				Non-human primate studies indicate that MPH treatment affects normal puberty. The transgenerational implications of this finding for humans needs to be followed-up	Mattison et al[155], 2011
G418 treatment (toxic stress)	Exposure of F0 females to G418 resulted in reduction of Polycomb group gene expression in up till F3 generation	Maternal Polycomb group expression in early embryogenesis affects expression of the zygotic genome, which can be inherited	Stern et al[168], 2014	G418 has been successfully used to rescue PTC deficiencies in a cell culture model for frontotemporal dementia. However, its broader utility for treating neuropsychiatric conditions remains unknown	Kuang et al[164], 2020
				PTC mutations of neuronal UPF3B gene associated with nonspecific mental retardation with or without austism	Laumonnier et al[183], 2010

PTC: Premature termination codon; IL: Interleukin.