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. 2018 Jun 1;32(11-12):742–762. doi: 10.1101/gad.311969.118

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© 2018 Schäfer et al.; Published by Cold Spring Harbor Laboratory Press

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Figure 7. — Gadd45a/Ing1 double-knockout mice phenocopy metabolic and ovarian defects of C/EBP mutants. (A) Body weight of male and female 8-wk-old mice from the indicated genotypes. Data are presented as mean values of n = 10–33 animals per sex and genotype ±SD. (**) P < 0.01; (***) P < 0.001. (DKO) Gadd45a/Ing1 double knockout. (B) Blood glucose levels of overnight fasted mice of the indicated genotypes. Each point represents an individual animal, and lines represent median values. n = 8–25 mice per genotype. (**) P < 0.01. (C) qPCR expression analysis of metabolic genes down-regulated in Cebp mutant livers in mice of the indicated genotypes. Data are presented as mean values of n = 8–13 samples per genotype ±SD. (*) P < 0.05; (**) P < 0.01. (D) Representative macroscopic view of mouse ovaries and uteri. n = 11–19 per genotype. Smaller ovaries were observed in 13 of 19 analyzed double-knockout mice. (E) Histological image (H&E stain) of mouse ovaries. n = 5 per genotype. The represented double-knockout phenotype was observed in four of five analyzed samples. (F) Percentage of cornified epithelial cells in vaginal smears, indicating estrus. n = 3–4 animals per genotype. Data from representative animals are shown. (G) A GADD45α–ING1–C/EBP axis regulates energy homeostasis, female fertility, adipogenesis, and organismal aging. GADD45α is an adapter protein for TET and TDG demethylation enzymes, while ING1 is a GADD45α-binding cofactor. In MEFs, GADD45α occupies C/EBP-dependent adipogenic superenhancers and promotes their demethylation via long-range interaction with ING1 bound to promoters to engage demethylating enzymes. Enhancer demethylation permits C/EBP binding and transactivation of target genes.