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Endocrinology ; 160(7): 1684-1700, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31150057

RESUMEN

Intrauterine exposure to various adverse conditions during fetal development can lead to epigenetic changes in fetal tissues, predisposing those tissues to disease conditions later in life. An example is gestational diabetes (GD), where the offspring has a higher risk of developing obesity, metabolic disorders, or cardiovascular disease in adult life. In this study, using two well-established GD (streptozotocin- and high-fat and high-sugar-induced) mouse models, we report that female offspring from GD dams are predisposed toward fertility problems later in life. This predisposition to fertility problems is due to altered ovarian expression of a peptide called cocaine- and amphetamine-regulated transcript (CART), which is known to negatively affect folliculogenesis and is induced by elevated leptin levels. Results show that the underlying cause of this altered expression is due to fetal epigenetic modifications involving glucose- and insulin-induced miRNA, miR-101, and the phosphatidylinositol 3-kinase/Akt pathway. These signaling events regulate Ezh2, a histone methyltransferase that promotes H3K27me3, a gene-repressive mark, and CBP/p300, a histone acetyltransferase that promotes H3K27ac, a transcription activation mark, in the fetal ovary. Moreover, the CART promoter has depleted 5-methylcytosine (5mC) and enriched 5-hydroxymethylcytosine (5hmC) levels. The depletion of H3K27me3 and 5mC repressive marks and subsequent increase in H3K27ac and 5hmC gene-activating marks convert the Cartpt promoter to a "superpromoter." This makes the Cartpt promoter more sensitive to leptin levels that predispose the GD offspring to fertility problems. Therefore, this study provides a mechanistic insight about fetal epigenome reprogramming that manifests to ovarian dysfunction and subfertility later in adult life.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Epigénesis Genética , Infertilidad/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Ovario/metabolismo , Regiones Promotoras Genéticas , Animales , Metilación de ADN , Diabetes Mellitus Experimental/genética , Diabetes Gestacional/genética , Femenino , Histonas/metabolismo , Infertilidad/genética , Ratones , Proteínas del Tejido Nervioso/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Embarazo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología
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