Visualizing changes in Cdkn1c expression links early life adversity to imprint mis-regulation in adults

Abstract

Imprinted genes are regulated accordin g 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 l oss . 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.