DNA methylation is the best studied epigenetic factor, playing a key role in producing stable changes in gene expression, thus defining cell identity and function and adapting cells to environmental changes. DNA methylation has also been recently shown to mediate cell responses to physiological endocrine signals. Moreover, alterations of the normal DNA methylation pattern can also contribute to the development of endocrine and metabolic diseases and can explain the relationship between an individual's genetic background, the environment, and disease. It should be remarked that although DNA methylation and demethylation are active processes, epigenetic changes produced during development can impact adult processes, establishing the idea that endocrine function can be persistently affected by events occurring in early life. Given the complexity of the endocrine system, both genetic and epigenetic processes, including DNA methylation, must be involved in its proper development and functioning. In this study, we summarize the recent knowledge in the field of DNA methylation and endocrinology. Given that DNA methylation can be involved in a number of endocrine and metabolic disorders, understanding and manipulating this modification opens a new door for preventing and treating endocrine diseases.
Verónica García-Carpizo, Lidia Ruiz-Llorente, Mario Fraga, and Ana Aranda
Julián Nevado, Stephan P Tenbaum, Ana Isabel Castillo, Aurora Sánchez-Pacheco, and Ana Aranda
The genetic predisposition of the host and the virus is the most important determinant for prediction of the course of human immunodeficiency virus type I (HIV-1) viral infection and acquired immune deficiency syndrome (AIDS) progression. Transcription from the HIV-1 long terminal repeat (LTR) is a crucial step for viral replication. Here, we describe a stimulatory role of the vitamin D receptor (VDR) on HIV-1 LTR transactivation. Transient transfections reveal that VDR activates the LTR in HeLa, U937, and Cos-1 cells in a ligand-dependent manner. 1α,25-Dihydroxyvitamin D3 (vitD3) promotes activation of a minimal LTR construct (from nucleotides −35 to +89), lacking a previously described hormone response element that binds several nuclear receptors. NF-κB (nuclear factor-kappa B) and Sp1-binding sites, which are responsible for most basal LTR activity in HeLa cells, are also dispensable for vitD3-dependent HIV-1 transcription. Although the tat response element element is not required for VDR-mediated HIV-1 gene expression, the viral protein Tat acts in a synergistic manner with the receptor to stimulate LTR activity. Furthermore, our data also show cooperation of the receptor with various cellular coactivators for HIV-1 transactivation by vitD3. Paradoxically, mutations in the VDR ligand-dependent transcriptional activation function-2 that abrogate vitD3-dependent stimulation through classical vitamin D response elements, do not reduce vitD3-mediated LTR transactivation. Furthermore, point mutations in the DNA-binding domain that abolish receptor binding to consensus DNA sequences do not affect ligand-dependent HIV-1 stimulation. These results show that VDR activates the HIV-1 LTR through different mechanisms, including non-classical nuclear receptor transcriptional actions that may ensure viral transcription under different physiological scenarios.