scholarly journals Synthetic α-Tocopherol, Compared with Natural α-Tocopherol, Downregulates Myelin Genes in Cerebella of Adolescent Ttpa-null Mice

2019 ◽  
Vol 150 (5) ◽  
pp. 1031-1040 ◽  
Author(s):  
Katherine M Ranard ◽  
Matthew J Kuchan ◽  
Richard S Bruno ◽  
Janice M Juraska ◽  
John W Erdman
Keyword(s):  
Gene Expression ◽  
Vitamin E ◽  
Target Genes ◽  
Limit Of Detection ◽  
High Dose ◽  
Regulatory Factor ◽  
Downstream Target ◽  
Transfer Protein ◽  
False Discovery ◽  
Myelin Gene

ABSTRACT Background Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. Objective We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-tocopherol transfer protein-null (Ttpa−/−) mice. Methods Three-week-old male Ttpa−/− mice (n  = 7/group) were fed 1 of 4 AIN-93G–based diets for 4 wk: vitamin E deficient (VED; below α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n  = 7). At 7 wk of age, tissue α-T concentrations and stereoisomer profiles were measured for all groups. RNA-sequencing was performed on cerebella of Ttpa−/− groups. Results Ttpa−/− mice fed VED had undetectable brain α-T concentrations. Cerebral cortex α-T concentrations were greater in Ttpa−/− mice fed NAT (9.1 ± 0.7 nmol/g), SYN (10.8 ± 1.0 nmol/g), and HSYN (13.9 ± 1.6 nmol/g) compared with the VED group but were significantly lower than in Ttpa+/+ mice fed CON (24.6 ± 1.2 nmol/g) (P < 0.001). RRR-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa−/− mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa−/− mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were differentially expressed. However, compared with the NAT diet, HSYN significantly downregulated 20 myelin genes, including 2 transcription factors: SRY-box transcription factor 10 (Sox10) and myelin regulatory factor (Myrf), and several downstream target genes (false discovery rate <0.05). Conclusions High-dose synthetic α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.

scholarly journals Genome-Wide Analysis of Glucocorticoid-Responsive Transcripts in the Hypothalamic Paraventricular Region of Male Rats

Endocrinology ◽  
2018 ◽  
Vol 160 (1) ◽  
pp. 38-54 ◽  
Author(s):  
Keiichi Itoi ◽  
Ikuko Motoike ◽  
Ying Liu ◽  
Sam Clokie ◽  
Yasumasa Iwasaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Receptor Gene ◽  
Male Rats ◽  
Regulatory Mechanisms ◽  
High Dose ◽  
Sequencing Analysis ◽  
Reverse Transcription Pcr ◽  
Genome Wide ◽  
A Genome

Abstract Glucocorticoids (GCs) are essential for stress adaptation, acting centrally and in the periphery. Corticotropin-releasing factor (CRF), a major regulator of adrenal GC synthesis, is produced in the paraventricular nucleus of the hypothalamus (PVH), which contains multiple neuroendocrine and preautonomic neurons. GCs may be involved in diverse regulatory mechanisms in the PVH, but the target genes of GCs are largely unexplored except for the CRF gene (Crh), a well-known target for GC negative feedback. Using a genome-wide RNA-sequencing analysis, we identified transcripts that changed in response to either high-dose corticosterone (Cort) exposure for 12 days (12-day high Cort), corticoid deprivation for 7 days (7-day ADX), or acute Cort administration. Among others, canonical GC target genes were upregulated prominently by 12-day high Cort. Crh was upregulated or downregulated most prominently by either 7-day ADX or 12-day high Cort, emphasizing the recognized feedback effects of GC on the hypothalamic-pituitary-adrenal (HPA) axis. Concomitant changes in vasopressin and apelin receptor gene expression are likely to contribute to HPA repression. In keeping with the pleotropic cellular actions of GCs, 7-day ADX downregulated numerous genes of a broad functional spectrum. The transcriptome response signature differed markedly between acute Cort injection and 12-day high Cort. Remarkably, six immediate early genes were upregulated 1 hour after Cort injection, which was confirmed by quantitative reverse transcription PCR and semiquantitative in situ hybridization. This study may provide a useful database for studying the regulatory mechanisms of GC-dependent gene expression and repression in the PVH.

scholarly journals Genomic dissection of the cytokine-controlled STAT5 signaling network in liver

2008 ◽  
Vol 34 (2) ◽  
pp. 135-143 ◽  
Author(s):  
Atsushi Hosui ◽  
Lothar Hennighausen
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Target Genes ◽  
Global Gene Expression ◽  
Specific Expression ◽  
Partial Explanation ◽  
Downstream Target ◽  
Expression Of Genes ◽  
Global Gene Expression Profiling

Growth hormone (GH) controls the physiology and pathophysiology of the liver, and its signals are conducted by two members of the family of signal transducers and activators of transcription, STAT5A and STAT5B. Mice in which the Stat5a/b locus has been inactivated specifically in hepatocytes display GH resistance, the sex-specific expression of genes associated with liver metabolism and the cytochrome P-450 system is lost, and they develop hepatosteatosis. Several groups have shown by global gene expression profiling that a cadre of STAT5A/B target genes identify genetic cascades induced by GH and other cytokines. Evidence is accumulating that in the absence of STAT5A/B GH aberrantly activates STAT1 and STAT3 and their downstream target genes and thereby offers a partial explanation of some of the physiological alterations observed in Stat5a/b-null mice and human patients. We hypothesize that phenotypic changes observed in the absence of STAT5A/B are due to two distinct molecular consequences: first, the failure of STAT5A/B target genes to be activated by GH and second, the rerouting of GH signaling to other members of the STAT family. Rerouting of GH signaling to STAT1 and STAT3 might partially compensate for the loss of STAT5A/B, but it certainly activates biological programs distinct from STAT5A/B. Here we discuss the extent to which studies on global gene expression profiling have fostered a better understanding of the biology behind cytokine-STAT5A/B networks in hepatocytes. We also explore whether this wealth of information on gene activity can be used to further understand the roles of cytokines in liver disease.

scholarly journals Determination of tissue-specific interaction between vitamin C and vitamin E in vivo using senescence marker protein-30 knockout mice as a vitamin C synthesis deficiency model

2021 ◽  
pp. 1-33
Author(s):  
Ayami Sato ◽  
Yuka Takino ◽  
Tomohiro Yano ◽  
Koji Fukui ◽  
Akihito Ishigami
Keyword(s):  
Gene Expression ◽  
Vitamin E ◽  
Vitamin C ◽  
Specific Interaction ◽  
Marker Protein ◽  
Tissue Specific ◽  
Transfer Protein

Abstract Vitamin E (α-tocopherol; VE) is known to be regenerated from VE radicals by vitamin C (L-ascorbic acid; VC) in vitro. However, their in vivo interaction in various tissues is still unclear. Therefore, we alternatively examined the in vivo interaction of VC and VE by measurement of their concentrations in various tissues of senescence marker protein-30 (SMP30) knockout (KO) mice as a VC synthesis deficiency model. Male SMP30-KO mice were divided into four groups (VC+/VE+, VC+/VE-, VC-/VE+, and VC-/VE-), fed diets with or without 500 mg/kg VE and given water with or without 1.5 g/L VC ad libitum. Then, VC and VE concentrations in the plasma and various tissues were determined. Further, gene expression levels of transporters associated with VC and VE, such as α-tocopherol transfer protein (α-TTP) and sodium-dependent vitamin C transporters (SVCTs), were examined. These results showed that the VE levels in the VC-depleted (VC-/VE+) group were significantly lower than those in the VC+/VE+ group in the liver and heart; the VC levels in the VE-depleted (VC+/VE-) group were significantly lower than those in the VC+/VE+ group in the kidneys. The α-TTP gene expression in the liver and kidneys were decreased by VC and/or VE depletion. Moreover, SVCT1 gene expression in the liver was decreased by both VC and VE depletion. In conclusion, these results indicate that VC spares VE mainly in the liver and heart, and that VE spares VC in the kidneys of SMP30-KO mice. Thus, interaction between VC and VE is likely to be tissue specific.

Abstract 835: Downregulation Of Cardiomyocyte-enriched Micrornas Contributes To Altered Gene Expression In Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Sadakatsu Ikeda ◽  
Sek Won Kong ◽  
Jun Lu ◽  
Egbert Bisping ◽  
Natalya Bodyak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Calcium Signaling ◽  
Target Genes ◽  
Heart Function ◽  
Altered Expression ◽  
Regulate Gene Expression ◽  
False Discovery ◽  
Altered Gene ◽  
Calmodulin Signaling

Background: MicroRNAs (miRNAs) are a novel class of non-coding RNAs that regulate gene expression posttransciptionally. Altered miRNA expression has been implicated in diverse human diseases such as cancer. Accumulating evidence suggests the importance of miRNAs in the heart. However, the contribution of miRNAs to heart disease remains incompletely understood. Methods and Results: We measured the expression of 261 miRNAs in heart failure resulting from transgenic overexpression of calcineurin. 59 miRNAs were confidently detected in the heart, and 11 miRNAs belonging to 6 families (miR-1, -15, -30, -133, -195, -208) were downregulated compared to non-transgenic control (Welch’s t-test nominal p<0.05, false discovery rate <0.001). The results were validated by qRTPCR. There was no upregulated miRNA. Four of these miRNAs (miR-1, -30, -133, -208) were enriched in a purified cardiomyocyte preparation, compared to non-myocytes. Downregulation of these four miRNAs was reproduced in purified failing versus non-failing cardiomyocytes. This excluded artifactual downregulation from reduced myocyte fraction in failing hearts. The remaining two miRNAs (miR-15, and -195) were exclusively expressed in non-cardiomyocytes and did not changed in failing cardiomyocytes. Next, we used Affymetrix expression profiling to show that the predicted targets of these downregulated miRNAs were disproportionately upregulated compared to the entire transcriptome (Fisher’s exact p < 0.001). This suggests an association between downregulation of these miRNAs and upregulation of predicted target genes in heart failure. One particularly intriguing target of the predominant cardiac microRNA miR-1 is calmodulin, a key regulator of calcium signaling. We showed that calmodulin and downstream calmodulin signaling to NFAT is regulated by miR-1 in cultured cardiomyocytes. Conclusion: Our results indicate that altered expression of cardiomyocyte-enriched miRNAs may contribute to abnormal gene expression in heart failure. The regulation of calmodulin and calcium signaling by miR-1 suggests a mechanism by which miR-1 may regulate heart function.

scholarly journals Induction of Human Liver X Receptor α Gene Expression Via an Autoregulatory Loop Mechanism

2002 ◽  
Vol 16 (3) ◽  
pp. 506-514 ◽  
Author(s):  
Yu Li ◽  
Charles Bolten ◽  
B. Ganesh Bhat ◽  
Jessica Woodring-Dietz ◽  
Suzhen Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Regulatory Element ◽  
Critical Role ◽  
Cell Types ◽  
Plasma Lipoproteins ◽  
Type I ◽  
Type Ii ◽  
Downstream Target ◽  
X Receptors

Abstract The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRα (hLXRα) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2–4 h. Analysis of the hLXRα promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRα:RXR and LXRβ:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRα:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRα and LXRβ activity, whereas the type II LXRE acts as a weaker and selective mediator of LXRα activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRα gene expression. This would lead to increased hLXRα levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.

scholarly journals Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

Neuron ◽  
2015 ◽  
Vol 85 (6) ◽  
pp. 1212-1226 ◽  
Author(s):  
Brenda Huang ◽  
WenJie Wei ◽  
Guohao Wang ◽  
Marta A. Gaertig ◽  
Yue Feng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mutant Huntingtin ◽  
Regulatory Factor ◽  
Myelin Gene

scholarly journals A synthetic oestrogen antagonist, tamoxifen, inhibits oestrogen-induced transcriptional, but not post-transcriptional, regulation of gene expression

1996 ◽  
Vol 313 (1) ◽  
pp. 269-274 ◽  
Author(s):  
Yukitomo ARAO ◽  
Etsuko YAMAMOTO ◽  
Naoto MIYATAKE ◽  
Yuichi NINOMIYA ◽  
Taisuke UMEHARA ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Oestrogen Receptor ◽  
Target Genes ◽  
Limit Of Detection ◽  
Regulation Of Gene Expression ◽  
Rapid Loss ◽  
Mrna Stabilization ◽  
Transcription Inhibitor ◽  
Post Transcriptional Regulation

Oestrogen (E2) regulates the expression of its target genes at transcriptional and post-transcriptional levels. To clarify the mechanism of E2-induced post-transcriptional regulation, with attention to the involvement of the oestrogen receptor (ER), we studied the effect of tamoxifen (TAM), a synthetic E2 antagonist that inhibits ER-mediated transcription, on E2-induced transcriptional and post-transcriptional regulation of the chicken ovalbumin (OVA) gene in chick oviducts. Run-on analysis with oviduct nuclei isolated from E2-treated chicks showed that TAM treatment completely blocked E2-induced transcription of the OVA gene within 24 h without affecting ER gene expression. Likewise, the rate of transcription fell to below the limit of detection after E2 withdrawal from the chicks. Reflecting the transcription rate, OVA mRNA accumulated linearly in E2-treated chicks, and E2 withdrawal caused a rapid loss of OVA mRNA. However, in the chicks treated with TAM and E2, OVA mRNA was degraded slowly over 48 h with a half-life of 24 h, suggesting that TAM does not inhibit E2-induced mRNA stabilization. Moreover, E2-induced mRNA stabilization was observed even when transcription of the OVA gene was blocked by a transcription inhibitor. Western-blot analysis showed that the remaining OVA mRNA was translatable. Thus the present study indicates that E2 regulates expression of the OVA gene via distinct pathways at transcriptional and post-transcriptional levels.

scholarly journals Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia

Development ◽  
2001 ◽  
Vol 128 (9) ◽  
pp. 1547-1558
Author(s):  
A.V. Tkatchenko ◽  
R.P. Visconti ◽  
L. Shang ◽  
T. Papenbrock ◽  
N.D. Pruett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Cluster ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hox Genes ◽  
Skin Condition ◽  
Hair Follicles ◽  
Keratin Gene ◽  
Downstream Target

Studying the roles of Hox genes in normal and pathological development of skin and hair requires identification of downstream target genes in genetically defined animal models. We show that transgenic mice overexpressing Hoxc13 in differentiating keratinocytes of hair follicles develop alopecia, accompanied by a progressive pathological skin condition that resembles ichthyosis. Large-scale analysis of differential gene expression in postnatal skin of these mice identified 16 previously unknown and 13 known genes as presumptive Hoxc13 targets. The majority of these targets are downregulated and belong to a subgroup of genes that encode hair-specific keratin-associated proteins (KAPs). Genomic mapping using a mouse hamster radiation hybrid panel showed these genes to reside in a novel KAP gene cluster on mouse chromosome 16 in a region of conserved linkage with human chromosome 21q22.11. Furthermore, data obtained by Hoxc13/lacZ reporter gene analysis in mice that overexpress Hoxc13 suggest negative autoregulatory feedback control of Hoxc13 expression levels, thus providing an entry point for elucidating currently unknown mechanisms that are required for regulating quantitative levels of Hox gene expression. Combined, these results provide a framework for understanding molecular mechanisms of Hoxc13 function in hair growth and development.

scholarly journals High Dose IFN-β Activates GAF to Enhance Expression of ISGF3 Target Genes in MLE12 Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Kensei Kishimoto ◽  
Catera L. Wilder ◽  
Justin Buchanan ◽  
Minh Nguyen ◽  
Chidera Okeke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Target Genes ◽  
Lung Epithelial Cells ◽  
High Dose ◽  
Sequence Motifs ◽  
Host Immune Responses ◽  
Interferon Stimulated Genes ◽  
Transcription Factor Complex

Interferon β (IFN-β) signaling activates the transcription factor complex ISGF3 to induce gene expression programs critical for antiviral defense and host immune responses. It has also been observed that IFN-β activates a second transcription factor complex, γ-activated factor (GAF), but the significance of this coordinated activation is unclear. We report that in murine lung epithelial cells (MLE12) high doses of IFN-β indeed activate both ISGF3 and GAF, which bind to distinct genomic locations defined by their respective DNA sequence motifs. In contrast, low doses of IFN-β preferentially activate ISGF3 but not GAF. Surprisingly, in MLE12 cells GAF binding does not induce nearby gene expression even when strongly bound to the promoter. Yet expression of interferon stimulated genes is enhanced when GAF and ISGF3 are both active compared to ISGF3 alone. We propose that GAF may function as a dose-sensitive amplifier of ISG expression to enhance antiviral immunity and establish pro-inflammatory states.

scholarly journals Systems biology-based investigation of cooperating microRNAs as monotherapy or adjuvant therapy in cancer

2019 ◽  
Vol 47 (15) ◽  
pp. 7753-7766 ◽  
Author(s):  
Xin Lai ◽  
Martin Eberhardt ◽  
Ulf Schmitz ◽  
Julio Vera
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Cell Phenotype ◽  
High Dose ◽  
Cancer Therapies ◽  
Mirna Therapeutics ◽  
Target Effects

Abstract MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.

Sign in / Sign up

Export Citation Format

Share Document