Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults.
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.
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Mathew
M
Van de Pette
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Allifia
A
Abbas
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Amelie
A
Feytout
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Gráinne
G
McNamara
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Ludovica
L
Bruno
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Wilson K
WK
To
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Andrew
A
Dimond
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Alessandro
A
Sardini
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Zoe
Z
Webster
Photonics Group, Department of Physics, Blackett Laboratory, Imperial College London, London SW7 2AZ, UK.
James
J
McGinty
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Eleanor J
EJ
Paul
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Mark A
MA
Ungless
Photonics Group, Department of Physics, Blackett Laboratory, Imperial College London, London SW7 2AZ, UK.
Paul M W
PMW
French
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Dominic J
DJ
Withers
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Anthony
A
Uren
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Anne C
AC
Ferguson-Smith
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Matthias
M
Merkenschlager
Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
Rosalind M
RM
John
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Electronic address: amanda.fisher@lms.mrc.ac.uk.
Amanda G
AG
Fisher
D000483:Alleles; D000818:Animals; D002843:Chromatin / Q000502:physiology; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology; D018392:Genomic Imprinting / Q000502:physiology*; D051379:Mice
C493965:Cdkn1c protein, mouse; D002843:Chromatin; D050761:Cyclin-Dependent Kinase Inhibitor p57
Cdkn1c; bioluminescence; environmental stress; imprinting; luciferase reporter mice