Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

ABSTRACT Hepatitis B virus X (HBX) is essential for the productive infection of hepatitis B virus (HBV) in vivo and has a pleiotropic effect on host cells. We have previously demonstrated that the proteasome complex is a cellular target of HBX, that HBX alters the proteolytic activity of proteasome in vitro, and that inhibition of proteasome leads to enhanced viral replication, suggesting that HBX and proteasome interaction plays a crucial role in the life cycle and pathogenesis of HBV. In the present study, we tested the effect of HBX on the proteasome activities in vivo in a transgenic mouse model in which HBX expression is developmentally regulated by the mouse major urinary promoter in the liver. In addition, microarray analysis was performed to examine the effect of HBX expression on the global gene expression profile of the liver. The results showed that the peptidase activities of the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation. In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a number of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX. In particular, insulin-like growth factor-binding protein 1 was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis virus infection. Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV infection.

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Effect of mild restriction of food intake on gene expression profile in the liver of young rats: reference data for in vivo nutrigenomics study

British Journal Of Nutrition ◽

10.1017/s0007114510001625 ◽

2010 ◽

Vol 104 (7) ◽

pp. 941-950 ◽

Cited By ~ 11

Author(s):

Kenji Saito ◽

Yutaka Ohta ◽

Manabu Sami ◽

Tomomasa Kanda ◽

Hisanori Kato

Keyword(s):

Gene Expression ◽

Food Intake ◽

Gene Expression Profile ◽

Expression Profile ◽

Fatty Acid Synthase ◽

Reference Data ◽

Global Gene Expression ◽

Energy Restriction ◽

Genes Encoding

Recent transcriptomics studies on the effect of long-term or severe energy restriction (ER) have revealed that many genes are dynamically modulated by this condition in rodents. The present study was conducted to define the global gene expression profile in response to mild ER treatment. Growing rats were fed with reduced amount of diet (5–30 % ER) for 1 week or 1 month. Using DNA microarray analysis of the liver, seventy-two genes that were consistently changed through the different ER levels were identified. Many were related to lipid metabolism including genes encoding key enzymes such as carnitine palmitoyltransferase 1 and fatty acid synthase. Interestingly, a number of genes were altered even by 5 % ER for 1 week where no differences in weight gain were observed. The information obtained in the present study can be used as a valuable reference data source in the transcriptomics studies of food and nutrition in which subtle differences in food intake sometimes hinder appropriate interpretation of the data.

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Abstract 4081: In vivo effects of decitabine on global gene expression profiles in tumors from patients with platinum-resistant ovarian cancer

10.1158/1538-7445.am2012-4081 ◽

2012 ◽

Author(s):

Fang Fang ◽

Jay Pilrose ◽

Changyu Shen ◽

Meng Li ◽

Daniela Matei ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Global Gene Expression ◽

Platinum Resistant ◽

In Vivo Effects

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Global Gene Expression Analysis of Long and Short Day 15 Bovine Conceptuses Produced In Vivo.

Biology of Reproduction ◽

10.1093/biolreprod/87.s1.192 ◽

2012 ◽

Vol 87 (Suppl_1) ◽

pp. 192-192

Author(s):

Callie V. Barnwell ◽

Christopher M. Ashwell ◽

Peter W. Farin ◽

William T. Farmer ◽

Charlotte E. Farin

Keyword(s):

Gene Expression ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Global Gene Expression ◽

Short Day ◽

Global Gene Expression Analysis

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Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00215.2001 ◽

2002 ◽

Vol 282 (1) ◽

pp. R173-R183 ◽

Cited By ~ 23

Author(s):

Min Nian ◽

Jun Gu ◽

David M. Irwin ◽

Daniel J. Drucker

Keyword(s):

Gene Expression ◽

Gene Promoter ◽

Regulatory Sequences ◽

Dependent Manner ◽

Specific Expression ◽

Tissue Specific ◽

High Fiber ◽

Fiber Diet ◽

Regulated Gene Expression

The glucagon-like peptides (GLPs) are synthesized and secreted in a nutrient-dependent manner in rodents; however, the factors regulating human GLP-1 and GLP-2 biosynthesis remain unclear. To understand how nutrients regulate human proglucagon gene expression, we studied the expression of a human proglucagon promoter-growth hormone (GH) transgene in 1.6 human glucagon-GH transgenic mice. Fasting-refeeding significantly decreased and increased the levels of circulating mouse insulin and transgene-derived hGH ( P < 0.05 fasting vs. refeeding) and decreased and upregulated, respectively, the levels of endogenous mouse proglucagon RNA in the ileum but not in the jejunum or colon. High-fiber feeding significantly increased the levels of glucose-stimulated circulating hGH and upregulated levels of mouse intestinal proglucagon gene expression in the jejunum, ileum, and colon ( P < 0.05, 0 vs. 30% fiber diet). In contrast, neither fasting-refeeding nor a high-fiber diet upregulated the expression of the human proglucagon promoter-hGH transgene. These findings demonstrate that human proglucagon gene regulatory sequences specifying tissue-specific expression in gut endocrine cells are not sufficient for recognition of energy-derived signals regulating murine glucagon gene expression in enteroendocrine cells in vivo.

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Hedgehog Signaling Inhibition by Smoothened Antagonist BMS-833923 Reduces Osteoblast Differentiation and Ectopic Bone Formation of Human Skeletal (Mesenchymal) Stem Cells

Stem Cells International ◽

10.1155/2019/3435901 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Nihal AlMuraikhi ◽

Nuha Almasoud ◽

Sarah Binhamdan ◽

Ghaydaa Younis ◽

Dalia Ali ◽

...

Keyword(s):

Gene Expression ◽

Bone Formation ◽

Osteoblast Differentiation ◽

Global Gene Expression ◽

Ectopic Bone Formation ◽

Ectopic Bone ◽

In Vitro Mineralization ◽

Global Gene Expression Profiling

Background. Hedgehog (Hh) signaling is essential for osteoblast differentiation of mesenchymal progenitors during endochondral bone formation. However, the critical role of Hh signaling during adult bone remodeling remains to be elucidated. Methods. A Smoothened (SMO) antagonist/Hedgehog inhibitor, BMS-833923, identified during a functional screening of a stem cell signaling small molecule library, was investigated for its effects on the osteoblast differentiation of human skeletal (mesenchymal) stem cells (hMSC). Alkaline phosphatase (ALP) activity and Alizarin red staining were employed as markers for osteoblast differentiation and in vitro mineralization capacity, respectively. Global gene expression profiling was performed using the Agilent® microarray platform. Effects on in vivo ectopic bone formation were assessed by implanting hMSC mixed with hydroxyapatite-tricalcium phosphate granules subcutaneously in 8-week-old female nude mice, and the amount of bone formed was assessed using quantitative histology. Results. BMS-833923, a SMO antagonist/Hedgehog inhibitor, exhibited significant inhibitory effects on osteoblast differentiation of hMSCs reflected by decreased ALP activity, in vitro mineralization, and downregulation of osteoblast-related gene expression. Similarly, we observed decreased in vivo ectopic bone formation. Global gene expression profiling of BMS-833923-treated compared to vehicle-treated control cells, identified 348 upregulated and 540 downregulated genes with significant effects on multiple signaling pathways, including GPCR, endochondral ossification, RANK-RANKL, insulin, TNF alpha, IL6, and inflammatory response. Further bioinformatic analysis employing Ingenuity Pathway Analysis revealed significant enrichment in BMS-833923-treated cells for a number of functional categories and networks involved in connective and skeletal tissue development and disorders, e.g., NFκB and STAT signaling. Conclusions. We identified SMO/Hedgehog antagonist (BMS-833923) as a powerful inhibitor of osteoblastic differentiation of hMSC that may be useful as a therapeutic option for treating conditions associated with high heterotopic bone formation and mineralization.

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