Chromatin modifiers MET-2 and SET-25 are required for behavioural and molecular inheritance after early-life toxic stress in C. elegans

Abstract

Stress exposure early in life is associated with behavioural and bodily changes that can develop several neuropsychiatric illnesses such as dementia. Experiences during the critical perinatal period form permanent, imprinted memories that can persistently alter expression levels of key genes through epigenetic marking, which can underpin changes in behaviour, molecular and stress responsivity throughout later life, including the next generations. Besides, this implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Although there are a number of studies in this field, there are still research gaps. For this reason, understanding the molecular mechanisms underlying the enduring effects of early-life stress is an important research area of the neuroscience. The aim of this project is to determine the behavioural and molecular changes and if there are changes in the epigenetic enzymes that can explain in part this phenomenon. Here using an experimental paradigm, we report that in response to early-life stresses, Caenorhabditis elegans nematodes form an imprinted behavioural and cellular defence memory. We show that exposing newly-born worms to toxic antimycin A exposure or repeated exposure, promotes aversive behaviour through chemotaxis assay and stimulates the expression of the hsp-6 enzyme a toxinspecific cytoprotective. Learned adult defences require memory formation during the L1 larval stage and do not appear to confer increased protection against the toxin. We found that aversive behaviour is inherited only to the F1 generation after 1 exposure to the toxic or can be passed to the F4 generation after 4 exposures to the toxic. At the molecular level, we found changes in the chromatin modifiers MET-2 and SET-25 as well as their target gene SKN-1 until the F3 generation after 1 exposure to the toxic or until the F5 generation after 4 exposures to the toxic stress. Furthermore, we found changes in the lifespan after 1 exposure in the F1 until F3 generations as well as in the F1 until F5 generations after 4 exposures to the toxic stimulus. Regarding the oxidative stress response, we found changes in the same generations after 1 exposure or after 4 exposures to early life toxic stress. Thus, exposure of Caenorhabditis elegans to toxic stresses in the critical period elicits adaptive behavioural and cytoprotective responses as we all as promote changes in the health outcomes, demonstrating a wide range of alterations that can appear after an early-life harmful stimulus. Likewise, we can conclude that these results are orchestrated by SET-25 pathway through SKN-1 transcription factor, which forms imprinted aversive behaviour and imprints a cytoprotective memory in the adulthood and the successive generations. These results, open a new avenue for new epigenetic therapies for neuropsychiatric disorders through chromatin