| 1. |
- Byrnes, Andrea, et al.
(författare)
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Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue : no evidence of a biomarker
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6, s. e5805-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes. METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays. FINDINGS: There were no significant differences in gene expression for any transcript. CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.
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| 2. |
- Jiao, Hong, et al.
(författare)
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Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity
- 2011
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 96:6, s. E962-E966
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Tidskriftsartikel (refereegranskat)abstract
- Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Setting: General community and referral centers for specialized care was the setting for the study. Participants: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. Main Outcome Measures: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. Results: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 x 10(-6), which was P = 7.0 x 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). Conclusions: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
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| 3. |
- Jiao, Hong, et al.
(författare)
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Genome wide association study identifies KCNMA1 contributing to human obesity
- 2011
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4, s. 51-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods: We performed a GWA analysis in 164 morbidly obese subjects (BMI: body mass index > 40 kg/m(2)) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for 14 adults. Results: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 x 10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C. I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 x 10(-17) and an OR of 1.36 [95% C. I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.
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| 4. |
- Brundin, Peik, et al.
(författare)
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Gene Expression of Estrogen Receptors in Pbmc From Patients With Puumala-Virus Infection
- 2012
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Ingår i: Shock. - Philadelphia : Lippincott Williams & Wilkins. - 1073-2322 .- 1540-0514. ; 37:4, s. 355-359
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Tidskriftsartikel (refereegranskat)abstract
- The influence of estrogen signaling on infectious diseases is not fully known. Males seem to be more susceptible to infections than females. This has also been noted for the Scandinavian form of hemorrhagic fever with renal syndrome caused by Puumala hantavirus (PUUV). To investigate the differences in estrogen receptors in relation to sex and clinical severity, 20 patients (10 males, 10 females) with confirmed PUUV infection were studied. Real-time polymerase chain reaction was performed for analyzing mRNA expression of estrogen receptor-alpha (ERV), ER beta, and ER beta 2 (ER beta cx) in peripheral blood mononuclear cells from patients and healthy age-and sex-matched blood donors. Blood chemistry and peripheral blood mononuclear cells sampling were performed during the acute and convalescent phases. None or very small amounts of ER beta were detected, and ER alpha and ER beta 2 mRNA were elevated in the patient group. The samples from the males were correlated with ER beta 2; the female samples, with ER alpha. Furthermore, the female and male samples are partly separated using multivariate statistic analysis (principal component analysis), supporting findings that clinical symptoms differ depending on sex.
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| 5. |
- Dahlman-Wright, Karin, et al.
(författare)
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Interplay between AP-1 and estrogen receptor α in regulating gene expression and proliferation networks in breast cancer cells
- 2012
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 33:9, s. 1684-91
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor α (ERα) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERα can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that c-Fos is a fundamental factor for ERα-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent proproliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERα can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross talk between AP-1 and estrogen signaling, we identify a novel ERα/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-β), which is overexpressed in ERα-positive breast cancer tissues. Knockdown of PKIB results in robust growth suppression of breast cancer cells. Collectively, our findings support c-Fos as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.
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| 6. |
- González-Bengtsson, Amanda, et al.
(författare)
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Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERa in Breast Cancer Cells
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine therapy is the first-line targeted adjuvant therapy for hormone-sensitive breast cancer. In view of the potential anticancer property of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) together with chemotherapy in estrogen receptor alpha (ER alpha) positive mammary tumors, we have explored the regulation by estradiol of the fatty acid desaturation and elongation enzymes involved in DHA synthesis in the human breast cancer cell line MCF7, which expresses ER alpha but not ER beta. We demonstrate a robust up-regulation in the expression of the fatty acid elongases Elovl2 and Elovl5 upon estradiol stimulation in MCF7 cells, which was sustained for more than 24 hours. Exposure with the ER inhibitor tamoxifen abolished specifically the Elovl2 but not the Elovl5 expression. Similarly, knockdown of ER alpha eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ER alpha binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ER alpha in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.
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| 7. |
- Goumidi, Louisa, et al.
(författare)
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Study of estrogen receptor-α and receptor-β gene polymorphisms on Alzheimer's disease.
- 2011
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 26:3, s. 431-9
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE ε4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (ε4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.
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| 8. |
- Gräns, Hanna, et al.
(författare)
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Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome.
- 2007
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 60:2, s. 195-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic fatigue syndrome (CFS) is an illness with unknown aetiology and pathophysiology. The difference in incidence by sex observed for CFS indicates a role for oestrogen and oestrogen receptors in disease development. Furthermore, an immunomediated pathogenesis has been suggested for CFS, providing an additional connection to oestrogen, which displays immunomodular functions. AIMS: To investigate a possible association of oestrogen receptor (ER) mRNAs and two ERbeta single-nucleotide polymorphisms (SNPs) with CFS. METHODS: Messenger RNA levels of ERalpha, ERbeta wt and ERbeta cx were investigated in peripheral blood mononuclear cells from 30 patients with CFS and 36 healthy controls by quantitative real-time polymerase chain reaction. Two ERbeta SNPs were scored in the same material. RESULTS: The CFS group showed significantly lower mRNA expression levels of ERbeta wt compared with the healthy control group. No differences were observed for ERalpha or ERbeta cx between patients and controls. There were no significant differences in frequency for the investigated ERbeta SNPs between cases and controls. CONCLUSIONS: The reduced ERbeta wt expression level observed in this study is consistent with an immune-mediated pathogenesis of CFS. Additionally, the observation that ERbeta wt expression is decreased in CFS could provide an entry point to identify interesting, potentially disease-causing, candidate molecules for further study. A possible connection between oestrogen, oestrogen receptors and CFS should be evaluated further.
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| 9. |
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| 10. |
- Jia, Min, et al.
(författare)
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Estrogen Receptor a Promotes Breast Cancer by Reprogramming Choline Metabolism
- 2016
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 76:19, s. 5634-5646
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ER alpha) is a key regulator of breast growth and breast cancer development. Here, we report how ER alpha impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ER alpha with estrogeninduced transcript and metabolic profiling, to demonstrate that ER alpha reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline (Cho) metabolism. Cho phosphotransfse CHPT1, identified as a direct era-regulated gene, was required for estrogen- induced effects on Cho metabolism, including increased phosphatidylcholine synthesis. CHPT1 silencing inhibited anchorage- independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that era promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target. (C) 2016 AACR.
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| 11. |
- Lappalainen, Tuuli, et al.
(författare)
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Genomic landscape of positive natural selection in Northern European populations.
- 2010
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 18:4, s. 471-478
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Tidskriftsartikel (refereegranskat)abstract
- Analyzing genetic variation of human populations for detecting loci that have been affected by positive natural selection is important for understanding adaptive history and phenotypic variation in humans. In this study, we analyzed recent positive selection in Northern Europe from genome-wide data sets of 250 000 and 500 000 single-nucleotide polymorphisms (SNPs) in a total of 999 individuals from Great Britain, Northern Germany, Eastern and Western Finland, and Sweden. Coalescent simulations were used for demonstrating that the integrated haplotype score (iHS) and long-range haplotype (LRH) statistics have sufficient power in genome-wide data sets of different sample sizes and SNP densities. Furthermore, the behavior of the F(ST) statistic in closely related populations was characterized by allele frequency simulations. In the analysis of the North European data set, 60 regions in the genome showed strong signs of recent positive selection. Out of these, 21 regions have not been discovered in previous scans, and many contain genes with interesting functions (eg, RAB38, INFG, NOS1AP, and APOE). In the putatively selected regions, we observed a statistically significant overrepresentation of genetic association with complex disease, which emphasizes the importance of the analysis of positive selection in understanding the evolution of human disease. Altogether, this study demonstrates the potential of genome-wide data sets to discover loci that lie behind evolutionary adaptation in different human populations.
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| 12. |
- Laurell, Cecilia, 1977-
(författare)
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Microarray Based Gene Expression Analysis in Cancer Research
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biotechnological inventions during the 20th century have resulted in a wide range of approaches for explorations in the functional genomics field. Microarray technology is one of the recent advances which have provided us with snapshots of which genes are expressed in cells of various tissues and diseases. Methods to obtain reliable microarray data are continuously being developed and improved to meet the demands of biological researchers.In this thesis microarrays have been used to investigate gene expression patterns in cancer research. Four studies in three different areas were carried out covering adrenocortical tumors, p53 target genes and a comparison of RNA amplification methods.Adrenocortical tumours are among the most common tumours with an incidence of 7-9%. Malignancy of these tumors is rare. Distinction between malignant and benign tumours is often difficult to establish which makes an improvement of diagnostic approaches important. To elucidate biological processes in adrenocortical tumour development and to examine if there is a molecular signature associated with malignancy, microarray analysis was performed on 29 adrenocortical tumors and four normal specimens. It was possible to classify malignant and benign samples based on the entire expression profile. A number of potential biomarkers was identified which will be further evaluated.P53 is a gene which is mutated in 50% of all cancers. Functional p53 is a transcription factor which is activated upon cellular stress and DNA damage. Target genes are mainly involved in cell cycle arrest and apoptosis. In solid tumors cells are stressed by hypoxia. To examine which target genes p53 activate under hypoxic conditions a microarray study of the cell lines HCT116p53+/+ and HCT116p53-/- was performed. A set of novel potential p53 target genes was identified while many known target genes were found to be not transcriptionally activated during hypoxia. Follow up which was focused on how p53 affected hypoxia induced apoptosis showed that the death receptor Fas was critical.When small amounts of tissue are available, amplification of the transcript population is necessary for microarray analysis. A new strategy for amplification based on PCR was evaluated and compared to a commercial in vitro transcription protocol. Both protocols produced reliable results. Advantages with the PCR based method are a lower cost and a high flexibility due to compatibility with both sense and antisense strand microarrays.Keywords: adrenocortical tumour, apoptosis, cancer, classification, gene expression, microarray, p53, RNA amplification
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| 13. |
- Leong, Gary M, et al.
(författare)
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Estrogen up-regulates hepatic expression of suppressors of cytokine signaling-2 and -3 in vivo and in vitro.
- 2004
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 145:12, s. 5525-31
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Tidskriftsartikel (refereegranskat)abstract
- Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-alpha, ERbeta, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERbeta knockout mice but not in those lacking ERalpha or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides -1862 and -855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERalpha, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.
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| 14. |
- Lindahl, Emma, et al.
(författare)
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Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells
- 2011
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Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 27:7, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.
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| 15. |
- Lindberg, Marie K, 1975, et al.
(författare)
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Estrogen receptor (ER)-beta reduces ERalpha-regulated gene transcription, supporting a "ying yang" relationship between ERalpha and ERbeta in mice.
- 2003
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Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 17:2, s. 203-8
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-beta (ERbeta) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERbeta-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERbeta-inactivated than in WT mice, demonstrating that ERbeta reduces estrogen receptor-alpha (ERalpha)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERalpha-inactivated mice was intermediate between that seen in WT and ERalphabeta double-inactivated mice. Thus, ERbeta inhibits ERalpha-mediated gene transcription in the presence of ERalpha, whereas, in the absence of ERalpha, it can partially replace ERalpha. In conclusion, our in vivo data indicate that an important physiological role of ERbeta is to modulate ERalpha-mediated gene transcription supporting a "Ying Yang" relationship between ERalpha and ERbeta in mice.
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| 16. |
- Lindberg, Marie K, 1975, et al.
(författare)
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Estrogen receptor specificity for the effects of estrogen in ovariectomized mice.
- 2002
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Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 174:2, s. 167-78
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen exerts a variety of important physiological effects, which have been suggested to be mediated via the two known estrogen receptors (ERs), alpha and beta. Three-month-old ovariectomized mice, lacking one or both of the two estrogen receptors, were given estrogen subcutaneously (2.3 micro g/mouse per day) and the effects on different estrogen-responsive parameters, including skeletal effects, were studied. We found that estrogen increased the cortical bone dimensions in both wild-type (WT) and double ER knockout (DERKO) mice. DNA microarray analysis was performed to characterize this effect on cortical bone and it identified four genes that were regulated by estrogen in both WT and DERKO mice. The effect of estrogen on cortical bone in DERKO mice might either be due to remaining ERalpha activity or represent an ERalpha/ERbeta-independent effect. Other effects of estrogen, such as increased trabecular bone mineral density, thymic atrophy, fat reduction and increased uterine weight, were mainly ERalpha mediated.
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| 17. |
- Lindberg, Marie K, 1975, et al.
(författare)
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Identification of estrogen-regulated genes of potential importance for the regulation of trabecular bone mineral density.
- 2002
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 0884-0431. ; 17:12, s. 2183-95
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen is of importance for the regulation of trabecular bone mineral density (BMD). The aim of this study was to search for possible mechanisms of action of estrogen on bone. Ovariectomized (OVX) mice were treated with 17beta-estradiol. Possible effects of estrogen on the expression of 125 different bone-related genes in humerus were analyzed using the microarray technique. Estrogen regulated 12 of these genes, namely, two growth factor-related genes, 8 cytokines, and 2 bone matrix-related genes. Five of the 12 genes are known to be estrogen-regulated, and the remaining 7 genes are novel estrogen-regulated genes. Seven genes, including interleukin-1 receptor antagonist (IL-1ra), IL-1receptor type II (IL-1RII), insulin-like growth factor-binding protein 4 (IGFBP-4), transforming growth factor beta (TGF-beta), granulocyte colony-stimulating factor receptor (G-CSFR), leukemia inhibitory factor receptor (LIFR), and soluble IL-4 receptor (sIL-4R) were selected as probable candidate genes for the trabecular bone-sparing effect of estrogen, as the mRNA levels of these genes were highly correlated (r2 > 0.65) to the trabecular BMD. The regulation of most of these seven genes was predominantly estrogen receptor alpha (ER-alpha)-mediated (5/7) while some genes (2/7) were regulated both via ER-alpha and ER-beta. In conclusion, by using the microarray technique, we have identified four previously known and three novel estrogen-regulated genes of potential importance for the trabecular bone-sparing effect of estrogen.
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| 18. |
- Lundholm, Lovisa, et al.
(författare)
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Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue: target genes include glutathione peroxidase 3 and cell death-inducing DNA fragmentation factor, alpha-subunit-like effector A.
- 2008
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 196:3, s. 547-57
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Tidskriftsartikel (refereegranskat)abstract
- Obesity has become a major health problem in many parts of the world. Estrogens are known to reduce adipose tissue mass in both humans and animals but the molecular mechanisms are not well characterized. We used gene expression profiling to study long-term effects of estrogen on gene expression in mouse white adipose tissue and hypothalamus. Overall, the effects of estrogen on hypothalamic gene expression were much smaller than the corresponding effects on white adipose tissue gene expression. We characterize in detail estrogenic regulation of glutathione peroxidase 3 (GPX3). Our studies suggest that GPX3 is a direct estrogen receptor alpha target gene in white adipose tissue. Since obesity is correlated with oxidative stress, and GPX3 has been demonstrated to be lower in obesity and higher after weight loss, we hypothesize that GPX3 is one important mediator of effects of estrogen in relation to fat mass. Additional genes that were affected by estrogen in adipose tissue include cell death-inducing DNA fragmentation factor, alpha-subunit-like effector A (CIDEA), a gene shown to be related to body fat in mice. We conclude that estrogen has large effects on gene expression in white adipose tissue and hypothesize that GPX3 and CIDEA could be important mediators of the effects of estrogen on fat mass.
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| 19. |
- Lundholm, Lovisa, et al.
(författare)
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Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue.
- 2004
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Ingår i: Journal of molecular endocrinology. - : Bioscientifica. - 0952-5041 .- 1479-6813. ; 32:3, s. 879-92
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens reduce adipose tissue mass in both humans and animals. The molecular mechanisms for this effect are, however, not well characterized. We took a gene expression profiling approach to study the direct effects of estrogen on mouse white adipose tissue (WAT). Female ovariectomized mice were treated for 10, 24 and 48 h with 17beta-estradiol or vehicle. RNA was extracted from gonadal fat and hybridized to Affymetrix MG-U74Av2 arrays. 17beta-Estradiol was shown to decrease mRNA expression of liver X receptor (LXR) alpha after 10 h of treatment compared with the vehicle control. The expression of several LXRalpha target genes, such as sterol regulatory element-binding protein 1c, apolipoprotein E, phospholipid transfer protein, ATP-binding cassette A1 and ATP-binding cassette G1, was similarly decreased. We furthermore identified a 1.5 kb LXRalpha promoter fragment that is negatively regulated by estrogen. Several genes involved in lipogenesis and lipolysis were identified as novel targets that could mediate estrogenic effects on adipose tissue. Finally, we show that ERalpha is the main estrogen receptor expressed in mouse white adipose tissue (WAT) with mRNA levels several hundred times higher than those of ERbeta mRNA.
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| 20. |
- Movérare, Sofia, et al.
(författare)
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Estrogen increases coagulation factor V mRNA levels via both estrogen receptor-alpha and -beta in murine bone marrow/bone.
- 2004
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 151:2, s. 259-63
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Both oral estrogen-based hormone-replacement therapy and contraceptives increase the risk of venous thromboembolism. Several circulating factors involved in coagulation/fibrinolysis are expressed mainly in the liver whilst some are expressed in extrahepatic tissues, including bone marrow. The aim of this study was to identify estrogen-responsive target genes involved in the pathogenesis of estrogen-induced venous thromboembolism. METHODS: Ovariectomized mice were treated with 17beta-estradiol and possible effects on the expression of genes related to coagulation/fibrinolysis were investigated using DNA microarray analyses. RESULTS: None of the selected genes was regulated by 17beta-estradiol in the liver. Interestingly, 17beta-estradiol increased mRNA levels of coagulation factor V in the bone marrow/bone. Furthermore, this stimulatory effect of 17beta-estradiol on coagulation factor V expression can be mediated via both estrogen receptor-alpha and -beta. CONCLUSIONS: The expression of bone marrow-derived, but not liver-derived, coagulation factor V is increased by estrogen treatment in mice. The pathophysiological importance of this finding for estrogen-induced venous thromboembolism remains to be determined.
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| 21. |
- Otsuki, Michio, et al.
(författare)
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Specific regulation of lipocalin-type prostaglandin D synthase in mouse heart by estrogen receptor beta.
- 2003
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Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 17:9, s. 1844-55
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens have important physiological roles in the cardiovascular system. We use DNA microarray technology to study the molecular mechanism of estrogen action in the heart and to identify novel estrogen-regulated genes. In this investigation we identify genes that are regulated by chronic estrogen treatment of mouse heart. We present our detailed characterization of one of these genes, lipocalin-type prostaglandin D synthase (L-PGDS). Northern and Western blot analysis revealed that L-PGDS was induced both by acute and chronic estrogen treatment. Northern blot analysis, using estrogen receptor (ER)-disrupted mice, suggests that L-PGDS is specifically induced by ERbeta in vivo. In further support of ERbeta-selective regulation, we identify a functional estrogen-responsive element in the L-PGDS promoter, the activity of which is up-regulated by ERbeta, but not by ERalpha. We demonstrate that a one-nucleotide change (A to C) in the L-PGDS estrogen-responsive element affects receptor selectivity.
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| 22. |
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| 23. |
- Salmela, Elina, et al.
(författare)
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Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe
- 2008
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Ingår i: PLOS ONE. - San Fransisco : Public library of science. - 1932-6203. ; 3:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide data provide a powerful tool for inferring patterns of genetic variation and structure of human populations.Principal Findings: In this study, we analysed almost 250,000 SNPs from a total of 945 samples from Eastern and Western Finland, Sweden, Northern Germany and Great Britain complemented with HapMap data. Small but statistically significant differences were observed between the European populations (F(ST) = 0.0040, p < 10(-4)), also between Eastern and Western Finland (F(ST) = 0.0032, p < 10(-3)). The latter indicated the existence of a relatively strong autosomal substructure within the country, similar to that observed earlier with smaller numbers of markers. The Germans and British were less differentiated than the Swedes, Western Finns and especially the Eastern Finns who also showed other signs of genetic drift. This is likely caused by the later founding of the northern populations, together with subsequent founder and bottleneck effects, and a smaller population size. Furthermore, our data suggest a small eastern contribution among the Finns, consistent with the historical and linguistic background of the population.Significance: Our results warn against a priori assumptions of homogeneity among Finns and other seemingly isolated populations. Thus, in association studies in such populations, additional caution for population structure may be necessary. Our results illustrate that population history is often important for patterns of genetic variation, and that the analysis of hundreds of thousands of SNPs provides high resolution also for population genetics.
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| 24. |
- Sinha, Indranil
(författare)
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Genome-wide patterns of histone modifications in fission yeast
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- DNA is wrapped almost two times around a group of proteins called histones to form a chromosomal structure known as the nucleosome. Both DNA and histones can be modified with different chemical tags by several enzymes to activate or suppress a particular gene or group of genes. Histones can be covalently modified at several places. Among many different types of post-translational histone modifications, histone acetylation and methylation are two important modification types that are associated with transcriptional activation and repression. Histone acetylation and methylation can be added by histone acetyltransferases (HATs) and histone methyletransferases (HMTs), whereas these modifications can be removed by histone deacetylases (HDACs) and histone demethylases (HDMs). Histone modifications are not only involved in the regulation of gene expression, but also in DNA-based processes, such as replication, repair, and the formation and maintenance of heterochromatin. Combinations of modified and unmodified states of histones can form distinct histone modification patterns. In many different genome-wide studies, it was observed that a distinctive pattern of histone modification in various organisms is important for gene regulation, DNA replication, chromosome segregation and heterochromatin-mediated silencing. In this thesis, we have conducted several genome-wide investigations to uncover different histone modification patterns and their roles in transcriptional control in fission yeast. Our analysis of six different HDACs in fission yeast showed that Clr6 and Clr3 are mainly involved in keeping repressed genes silent; Sir2 and Hst2 repress non-expressed genes, and Hst4 acts globally to reduce gene expression, whereas Hos2 is required for the activation of gene expression. By investigating the influence of each HDAC on nucleosome density, we found that all sirtuins and Hos2 enzymes are required to maintain normal nucleosome density and distribution in the S. pombe genome. We have reported that histone acetylation patterns show a 5` to 3` polarity, i.e., the modification levels peak near the ATG and gradually decrease in the coding regions. We also found that histone acetylation patterns depend on gene expression but are independent of gene length. Comparing our data with other published datasets, we observed that different HDAC mutants affect acetylation in different parts of open reading frames (ORFs). We have demonstrated that histone H4 acetylation proceeds in the direction from K16 to K5, consistent with a `zip` model that may be involved in transcriptional control. Our analysis revealed antagonistic crosstalk between H3K36me2/me3 and H3K27ac at promoter regions. We observed that histone H3 K18, K27 and K9 acetylation positively correlate with gene expression, and a conserved pattern was also reported in other organisms. Finally, we report that histone H4K20me1 is strongly linked to active genes, whereas H4K20me3 is associated with weakly expressed genes. Our analysis further shows that H4K20me1 modification levels peak at 3‟UTR regions in active genes. Thus, our analysis revealed many different aspects of histone modification patterns and their roles in transcriptional control in fission yeast.
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| 25. |
- Zhao, Chunyan, et al.
(författare)
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Estrogen receptor beta 2 negatively regulates the transactivation of estrogen receptor alpha in human breast cancer cells
- 2007
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:8, s. 3955-3962
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens, by binding to and activating two estrogen receptors (ER alpha and ER beta), are critically involved in the development of the mammary gland and breast cancer. An isoform of ER beta, ER beta 2 (also called ER beta cx), with an altered COOH-terminal region, is coexpressed with ER alpha. in many human breast cancers. In this study, we generated a stable cell line from MCF7 breast cancer cells expressing an inducible version of ER beta 2, along with endogenous ER alpha, and examined the effects of ER beta 2 on the ER alpha protein levels and function. We showed that ER beta 2 inhibited ER alpha-mediated transactivation via estrogen response element and activator protein-1 sites of reporter constructs as well as the endogenous genes pS2 and MMP-1. Chromatin immunoprecipitation assays revealed that ER beta 2 expression caused a significant reduction in the recruitment of ER alpha to both the pS2 and MMP-1 promoters. Furthermore, ER beta 2 expression induced proteasome-dependent degradation of ER alpha. The inhibitory effects of ER beta 2 on ER alpha activity were further confirmed in HEK293 cells that lack functional endogenous ER alpha. We also showed that ER beta 2 can interact with ER alpha both in vitro and in mammalian cells' which is compatible with a model where ER beta 2/ER alpha heterodimers are targeted to the proteasome. Finally, in human breast cancer samples, we observed that expression of ER beta 2 significantly correlated with ER alpha-negative phenotype. Our data suggest that ER beta 2 could influence ER alpha-mediated effects relevant for breast cancer development, including hormone responsiveness.
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| 26. |
- Zhao, Chunyan, et al.
(författare)
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Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.
- 2014
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:14, s. 3983-3994
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.
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