Deletion of exons 3 and 4 in the mouse Nr1d1 gene worsens high-fat diet-induced hepatic steatosis.

AIMS: To elucidate the role of nuclear receptor subfamily 1, group D, member 1 (Nr1d1) in hepatic lipid metabolism and pathogenesis of nonalcoholic fatty liver diseases, Nr1d1 gene mutant mice, in which the DNA-binding domain (exons 3 and 4) was deleted (Nr1d1 Δex3/4), were challenged with a high-fat diet (HFD), and the gene expression patterns that responded to this alteration were profiled. MAIN METHODS: The Nr1d1 Δex3/4 mice were fed an HFD for 12weeks. Liver tissues were examined by histology, and lipid droplets were detected by Oil-Red O staining. Serum biochemical analyses were performed to assess markers of liver injury. Microarray analysis was used to profile hepatic gene expression patterns. Functional annotation, upstream prediction, and gene coexpression prediction analyses were performed. KEY FINDINGS: The Nr1d1 Δex3/4 mice showed enhanced hepatic steatosis after being challenged with an HFD, but not with a low-fat diet, indicating an interaction between diet and genotype for this phenotypic change. Gene expression profiling revealed that this interaction might involve neutrophil recruitment and the cyclic adenosine monophosphate metabolic pathway. A study of transcription factor binding site enrichment suggested that CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha were associated with this phenotypic change. SIGNIFICANCE: Loss of DNA binding of Nr1d1 was associated with a deterioration in hepatic steatosis. The interaction between the Nr1d1 Δex3/4 genotype with an HFD might mediate these phenotypic changes, probably through a nonclassical transcriptional function of Nr1d1.

Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.

Metastasis-associated protein 1 (MTA1) is a component of the nucleosome remodeling and histone deacetylase (HDAC) complex, which plays an important role in progression of breast cancer. Although MTA1 is known as a repressor of the transactivation function of estrogen receptor α (ERα), its involvement in the epigenetic control of transcription of the ERα gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ERα in ERα-positive cells but increased it in ERα-negative cells. In both MCF7 and MDA-MB-231, MTA1 was recruited to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2γ (TFAP2C) and the IFN-γ-inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERα mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ERα. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERα. Finally, an MDA-MB-231-derived cell line that stably expressed shIFI16 or shMTA1 was more susceptible to tamoxifen-induced growth inhibition in in vitro and in vivo experiments. Taken together, our findings suggest that the MTA1-TFAP2C or the MTA1-IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer and may determine the chemosensitivity of tumors to tamoxifen therapy in patients with breast cancer.