Gene Expression 

About: Gene Expression is an academic journal published by Cognizant, LLC. The journal publishes majorly in the area(s): Gene & Transcription factor. It has an ISSN identifier of 1052-2166. Over the lifetime, 529 publications have been published receiving 16721 citations. The journal is also known as: Gene expression, the journal of liver research & Gene expression, the journal of basic liver research.

The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation.

Abstract: Posttranslational modifications of histones in chromatin are emerging as an important mechanism in the regulation of gene expression. Changes in histone acetylation levels occur during many nuclear processes such as replication, transcriptional silencing, and activation. Histone acetylation levels represent the result of a dynamic equilibrium between competing histone deacetylase(s) and histone acetylase(s). We have used two new specific inhibitors of histone deacetylase, trichostatin A (TSA) and trapoxin (TPX), to probe the effect of histone hyperacetylation on gene expression. We confirm that both drugs block histone deacetylase activity and have no detectable effects on histone acetylation rates in human lymphoid cell lines. Treatment with either TSA or TPX results in the transcriptional activation of HIV-1 gene expression in latently infected cell lines. In contrast, TSA and TPX cause a rapid decrease in c-myc gene expression and no change in the expression of the gene for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using differential display to compare the differences in gene expression between untreated cells and cells treated with TSA, we found that the expression of approximately 2% of cellular genes (8 genes out of approximately 340 examined) changes in response to TSA treatment. These results demonstrate that the transcriptional regulation of a restricted set of cellular genes is uniquely sensitive to the degree of histone acetylation in chromatin.

ATF3 and stress responses.

Abstract: The purpose of this review is to discuss ATF3, a member of the ATF/CREB family of transcription factors, and its roles in stress responses. In the introduction, we briefly describe the ATF/CREB family, which contains more than 10 proteins with the basic region-leucine zipper (bZip) DNA binding domain. We summarize their DNA binding and heterodimer formation with other bZip proteins, and discuss the nomenclature of these proteins. Over the years, identical or homologous cDNA clones have been isolated by different laboratories and given different names. We group these proteins into subgroups according to their amino acid similarity; we also list the alternative names for each member, and clarify some potential confusion in the nomenclature of this family of proteins. We then focus on ATF3 and its potential roles in stress responses. We review the evidence that the mRNA level of ATF3 greatly increases when the cells are exposed to stress signals. In animal experiments, the signals include ischemia, ischemia coupled with reperfusion, wounding, axotomy, toxicity, and seizure; in cultured cells, the signals include serum factors, cytokines, genotoxic agents, cell death-inducing agents, and the adenoviral protein E1A. Despite the overwhelming evidence for its induction by stress signals, not much else is known about ATF3. Preliminary results suggest that the JNK/SAPK pathway is involved in the induction of ATF3 by stress signals; in addition, IL-6 and p53 have been demonstrated to be required for the induction of ATF3 under certain conditions. The consequences of inducing ATF3 during stress responses are not clear. Transient transfection and in vitro transcription assays indicate that ATF3 represses transcription as a homodimer; however, ATF3 can activate transcription when coexpressed with its heterodimeric partners or other proteins. Therefore, it is possible that, when induced during stress responses, ATF3 activates some target genes but represses others, depending on the promoter context and cellular context. Even less is understood about the physiological significance of inducing ATF3. We will discuss our preliminary results and some reports by other investigators in this regard.

Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha.

Abstract: Hypoxia inducible factors (HIFs) are heterodimeric transcription factors that regulate a number of adaptive responses to low oxygen tension. They are composed of alpha- and beta-subunits that belong to the basic helix-loop-helix-PAS (bHLH-PAS) superfamily. In our efforts to identify new bHLH-PAS proteins, we cloned a cDNA encoding a novel alpha-class hypoxia inducible factor, HIF3alpha. The HIF3alpha open reading frame encodes a 662-amino acid protein with a predicted molecular weight of 73 kDa and is expressed in adult thymus, lung, brain, heart, and kidney. The N-terminal bHLH-PAS domain of this protein shares amino acid sequence identity with that of HIF1alpha and HIF2alpha (57% and 53% identity, respectively). The C-terminus of HIF3alpha contains a 36-amino acid sequence that shares 61% identity with the hypoxia responsive domain-1 (HRD1) of HIF1alpha. In transient transfections, this domain confers hypoxia responsiveness when linked to a heterologous transactivation domain. In vitro studies reveal that HIF3alpha dimerizes with a prototype beta-class subunit, ARNT, and that the resultant heterodimer recognizes the hypoxia responsive element (HRE) core sequence, TACGTG. Transient transfection experiments demonstrate that the HIF3alpha-ARNT interaction can occur in vivo, and that the activity of HIF3alpha is upregulated in response to cobalt chloride or low oxygen tension.

Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping.

Abstract: The nuclear receptor superfamily of transcription factors, which includes the retinoic acid receptors and v-erb A, play important roles in the molecular control of hematopoiesis To identify nuclear receptors expressed in hematopoietic cells, we screened a human bone marrow cDNA library using a degenerate oligonucleotide and isolated a 185-kb full-length cDNA encoding a new human member of this superfamily, the peroxisome proliferator activated receptor gamma (hPPAR gamma) Two different hPPAR gamma transcripts were expressed in hematopoietic cells: a 185-kb transcript, which corresponds to the full-length mRNA (PPAR gamma 1), and a 065-kb transcript (PPAR gamma 2), which cannot encode all of the nuclear receptor functional domains Normal neutrophils and peripheral blood lymphocytes, as well as circulating leukemic cells from patients with AML, ALL, and CML, express only PPAR gamma 2 on Northern blot analysis In contrast, only the PPAR gamma 1 transcript was detected in a variety of human leukemia cell lines and in cultured normal primary bone marrow stromal cells Both transcripts were detected in various fetal and adult nonhematopoietic tissues We mapped the location of the hPPAR gamma gene to human chromosome 3p25 by somatic cell hybridization and linkage analysis PPARs have been shown to be activated by peroxisome proliferating agents, long-chain fatty acids and arachidonic acid Human PPAR gamma, although homologous to the PPAR gamma s of other species, has unique sequence and amino acid differences Identification of hPPAR gamma will allow further understanding of its role in human cellular leukotriene, prostaglandin, and peroxide degradative or synthetic pathways, as well as its role in lipid metabolism and regulation of adipocyte differentiation

Bile Acid Metabolism in Liver Pathobiology.

Abstract: Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders.