期刊
CELL REPORTS
卷 18, 期 5, 页码 1090-1099出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.010
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资金
- MRC [MR/M013960/1]
- European Research Council
- Wellcome Trust
- NIHR Imperial BRC
- BBSRC grant [BB/J015156]
- ERC Advanced Grant [294627]
- MRC [MR/K011561/1, MR/M013960/1, MC_U120027516, MC_U120085816, MC_U120097114, MC_UP_A652_1001] Funding Source: UKRI
- Medical Research Council [MC_U120085816, MC_UP_A652_1001, 1116184, MC_U120027516, MR/K011561/1, MC_U120097114, MR/M013960/1, 1375663] Funding Source: researchfish
- National Institute for Health Research [ACF-2016-18-023] Funding Source: researchfish
- European Research Council (ERC) [294627] Funding Source: European Research Council (ERC)
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.
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