Magnesium deficiency affects HNF1ß expression in rat liver in vivo and in vitro.

Hepatocyte nuclear factor 1ß (HNF1ß) is a transcription factor that is involved in embryonic development and tissue-specific gene expression in several organs, including the kidney and the liver. HNF1ß mutations are associated with hypomagnesemia and renal magnesium wasting; however, to date, the exact molecular mechanism involved in this regulation is unclear. Furthermore, it is not known whether the Mg concentration could per se participate to this regulation by modifying HNF1ß expression. We have studied in rats the effects of a 6-week diet with deficient or supplemented Mg concentrations compared to a diet with a standard Mg concentration on HNF1ß protein expression. HNF1ß expression was increased in the Mg-deficient group as compared to the other groups in the liver but not in the kidney. No changes in tissue Mg level were obtained in both organs. By contrast, a significant correlation between plasma Mg concentration and HNF1ß level in the rat liver was evidenced. In rat hepatocyte cultures exposed for 72h to various extracellular Mg concentrations, HNF1ß expression was modified after 72h of treatment of the hepatocytes with the lowest Mg concentrations as compared to the other Mg conditions. Moreover, these changes were correlated with extracellular but not intracellular Mg concentrations. In conclusion, HNF1ß expression is modified by the extracellular Mg concentration in the liver, both in vivo and in vitro, suggesting regulations with membrane events in hepatocytes.

Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases.

BACKGROUND: The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood. RESULTS: In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity and decreases PLZF transcriptional repression. As a result, the chromatin status of the promoters of PLZF target genes, involved in oncogenesis, shift from a heterochromatin to an open euchromatin environment leading to gene expression even in the presence of PLZF. CONCLUSIONS: Consequently, SIRT1 and HDAC3 mediated-PLZF deacetylation provides for rapid control and fine-tuning of PLZF activity through post-transcriptional modification to regulate gene expression and cellular homeostasis.