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

Van de Pette, Mathew, Abbas, Allifia, Feytout, Amelie, McNamara, Gráinne, Bruno, Ludovica, To, Wilson K., Dimond, Andrew, Sardini, Alessandro, Webster, Zoe, McGinty, James, Paul, Eleanor J., Ungless, Mark A., French, Paul M.W., Withers, Dominic J., Uren, Anthony, Ferguson-Smith, Anne C., Merkenschlager, Matthias, John, Rosalind Margaret and Fisher, Amanda G. 2017. Visualizing changes in Cdkn1c expression links early-Life adversity to imprint mis-regulation in adults. Cell Reports 18 (5) , pp. 1090-1099. 10.1016/j.celrep.2017.01.010

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Publisher: Cell Press
ISSN: 2211-1247
Date of First Compliant Deposit: 9 March 2017
Date of Acceptance: 7 January 2017
Last Modified: 04 Jun 2017 09:44
URI: http://orca.cf.ac.uk/id/eprint/98876

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