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

Cell Rep. 2017 Jan 31;18(5):1090-1099. doi: 10.1016/j.celrep.2017.01.010.

Abstract

Imprinted 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.

Keywords: Cdkn1c; bioluminescence; environmental stress; imprinting; luciferase reporter mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Chromatin / physiology
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism*
  • DNA Methylation / physiology
  • Epigenesis, Genetic / physiology
  • Genomic Imprinting / physiology*
  • Mice

Substances

  • Cdkn1c protein, mouse
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p57