Glucocorticoid-induced DNA demethylation and gene memory during development

Abstract

Glucocorticoid hormones were found to regulate DNA demethylation within a key enhancer of the rat liver-speci®c tyrosine aminotransferase (Tat) gene. Genomic footprinting analysis shows that the glucocorticoid receptor uses local DNA demethylation as one of several steps to recruit transcription factors in hepatoma cells. Demethylation occurs within 2±3 days following rapid (<1 h) chromatin remodeling and recruitment of a ®rst transcription factor, HNF-3. Upon demethylation, two additional transcription factors are recruited when chromatin is remodeled. In contrast to chromatin remodeling, the demethylation is stable following hormone withdrawal. As a stronger subsequent glucocorticoid response is observed, demethylation appears to provide memory of the ®rst stimulation. During development, this demethylation occurs before birth, at a stage where the Tat gene is not yet inducible, and it could thus prepare the enhancer for subsequent stimulation by hypoglycemia at birth. In vitro cultures of fetal hepatocytes recapitulate the regulation analyzed in hepatoma cells. Therefore, demethylation appears to contribute to the ®ne-tuning of the enhancer and to the memorization of a regulatory event during development.

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

“…Abnormal expression of the lactoferrin and c-fos genes in the endometrium of adult CD-1 mice developmentally exposed to DES correlates with an altered pattern of CpG methylation in these genes (13,15,38). DNA methylation has also been shown to provide memory of the first hormone induction during development (39). The tyrosine aminotransferase (Tat) gene is induced in rat fetal hepatocytes by exposure to glucocorticoids.…”

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks

“…We analyzed the demethylation occurring at a glucocorticoid-responsive unit (GRU) located 2.5 kb upstream of the transcription start site of the tyrosine aminotransferase (Tat) gene upon activation by the glucocorticoid receptor. This event takes place in the liver before birth and is involved in the memorization of the first stimulation of the gene by glucocorticoids (19). We demonstrate that demethylation of cytosines at this gene under physiological conditions results from an active mechanism that involves the creation of nicks in the DNA 3Ј to the methylcytidine.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Leptin, a key gene in energy balance regulation, is hypomethylated in whole blood of humans being born small for gestational age due to prenatal growth restriction early in pregnancy (Tobi et al, 2011). Glucocorticoids, which affect food intake and abdominal obesity, cause local DNA demethylation of the tyrosine aminotransferase gene around a glucocorticoid response element that appears to contribute to the memorization of long-term effects of glucocorticoids in neonatal brains (Thomassin et al, 2001). According to these encouraging data, more emphasis must be made in the study of the epigenetic alterations due to transient or chronic hormonal imbalances, which are so common in obesity and related comorbidities, as well as in the knowledge of the epigenetic mechanisms that regulate the secretion of hormones as a result of dietary and environmental factors.…”