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

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.