Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults

Abstract

SummaryImprinted genes are regulated according to parental origin and can influence embryonic growth and metabolism and confer disease susceptibility. Here, we designed sensitive allele-specific reporters to non-invasively monitor imprinted Cdkn1c expression in mice and showed that expression was modulated by environmental factors encountered in utero. Acute exposure to chromatin-modifying drugs resulted in de-repression of paternally inherited (silent) Cdkn1c alleles in embryos that was temporary and resolved after birth. In contrast, deprivation of maternal dietary protein in utero provoked permanent de-repression of imprinted Cdkn1c expression that was sustained into adulthood and occurred through a folate-dependent mechanism of DNA methylation loss. Given the function of imprinted genes in regulating behavior and metabolic processes in adults, these results establish imprinting deregulation as a credible mechanism linking early-life adversity to later-life outcomes. Furthermore, Cdkn1c-luciferase mice offer non-invasive tools to identify factors that disrupt epigenetic processes and strategies to limit their long-term impact.

Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c

“…For the case of both low maternal dietary proteins, this appears to be due to de‐repression of the normally silent paternally inherited allele of Cdkn1c (Van de Pette et al . ). Both of these early life manipulations are associated with changes in the dopamine system and the response to reward (Pena et al .…”

“…Additionally, as the expression of rodent Cdkn1c is sensitive to maternal diet (Van de Pette et al . ; Vucetic et al . ) and postnatal care (Pena et al .…”

“…; Van de Pette et al . ; Vucetic et al . ), shows a potential role of the imprinted gene Cdkn1c in mediating the changes dopaminergic function seen following such adverse early life events.…”

“…Although we can not draw conclusive causal relationships between elevated Cdkn1c, altered neurobiology and the observed behavioural phenotypes, this work underlines the importance of correct imprinted gene expression for brain and behaviour. Additionally, as the expression of rodent Cdkn1c is sensitive to maternal diet (Van de Pette et al 2017;Vucetic et al 2010b) and postnatal care (Pena et al 2014), dysregulation of this gene may underpin some aspects of the neural and behavioural phenotypic consequences associated these adverse early life environments.…”

“…Specifically, both low maternal dietary protein (Vucetic et al 2010b), and the degree of postnatal maternal care (Pena et al 2014) lead to increased Cdkn1c expression in the brain. For the case of both low maternal dietary proteins, this appears to be due to de-repression of the normally silent paternally inherited allele of Cdkn1c (Van de Pette et al 2017). Both of these early life manipulations are associated with changes in the dopamine system and the response to reward (Pena et al 2014;Vucetic et al 2010b).…”