Alpha Gene Promoter Research Articles

Tumor Necrosis Factor Alpha (TNFα) Gene Promoter Polymorphisms and Haplotypes are Associated with the Febrile Seizure (FS) and TNFα Serum Levels.

Febrile seizure (FS) is a neuroinflammatory disease involving fever-induced seizures affecting children in the early stages of life. TNFα is a pro-inflammatory cytokine reported to be elevated in FS. Specific promoter variants of TNFα could be associated with its elevated cytokine expression and susceptibility to FS. The present study analyzed the association of specific TNFα variants, including TNFα -238 G/A (rs361525), TNFα -308 G/A (rs1800629), and TNFα -376 G/A (rs1800750) promoter polymorphisms, with FS susceptibility, and TNFα serum levels in an Iranian population. Sixty-eight FS patients and 136 controls were enrolled. The SSP-PCR method was utilized to analyze TNFα promoter genotypes. This research also confirmed the genotyping results by sequencing samples of ten patients and normal controls. The GG genotype of -238 SNP was associated with the increased risk of FS [OR = 12.65, 95% CI (2.83-56.60), P-value = 0.0012]. The AA genotype in the-308 region was increased in patients with FS and associated with the disease [OR = 4.62, 95% CI (1.46-14.56), P-value = 0.028]. The increased occurrence of heterozygous AG in the -376 SNP among control groups has been linked to a decreased risk of FS [OR = 0.22, 95% CI (0.11-0.43), P-value = 0.0001]. This study revealed that AGA (-238/ -308/ -376) haplotype with the highest frequency in controls was associated with a decreased risk of FS, while GAA (-238/ -308/ -376) carriers were more susceptible to FS. The current study suggested that TNFα gene promoter variants at rs361525, rs1800629, and rs1800750 could be associated with the susceptibility to FS and altered serum levels of TNFα.

Genetic study of I kappa B alpha gene promoter polymorphism associated with hepatitis C virus in Egyptian patients

Genetic study of I kappa B alpha gene promoter polymorphism associated with hepatitis C virus in Egyptian patients

Exercise Modalities Improve Aversive Memory and Survival Rate in Aged Rats: Role of Hippocampal Epigenetic Modifications.

We aimed to investigate the effects of aging and different exercise modalities on aversive memory and epigenetic landscapes at brain-derived neurotrophic factor, cFos, and DNA methyltransferase 3 alpha (Bdnf, cFos, and Dnmt3a, respectively) gene promoters in hippocampus of rats. Specifically, active epigenetic histone markers (H3K9ac, H3K4me3, and H4K8ac) and a repressive mark (H3K9me2) were evaluated. Adult and aged male Wistar rats (2 and 22months old) were subjected to aerobic, acrobatic, resistance, or combined exercise modalities for 20min, 3 times a week, during 12weeks. Aging per se altered histone modifications at the promoters of Bdnf, cFos, and Dnmt3a. All exercise modalities improved both survival rate and aversive memory performance in aged animals (n= 7-10). Exercise altered hippocampal epigenetic marks in an age- and modality-dependent manner (n= 4-5). Aerobic and resistance modalities attenuated age-induced effects on hippocampal Bdnf promoter H3K4me3. Besides, exercise modalities which improved memory performance in aged rats were able to modify H3K9ac or H3K4me3 at the cFos promoter, which could increase gene transcription. Our results highlight biological mechanisms which support the efficacy of all tested exercise modalities attenuating memory deficits induced by aging.

Methylation Status of Promoter Region of Tumor Necrosis Factor Alpha Gene in Subjects with Healthy Gingiva and Chronic Periodontitis - A Pilot Study.

Periodontitis is a multi-factorial disease with bacterial origin. The progression is influenced by systemic disease, smoking, genetic factors. In the recent past epigenetic influences have been indentified on the candidate genes which code for proteins that play a role in the pathogenesis of the periodontal disease. Epigenetic mechanisms involve DNA methylation and histone modification. Till date, there is no existing data associating methylation status of the promoter region (-239, -245) of the TNF alpha gene and chronic periodontitis. The objective of this study was to compare the methylation status of CpG islands in the promoter region of TNF alpha (-239, -245) gene in the peripheral blood among subjects with healthy gingiva and chronic periodontitis. A case control study design involving 50 subjects (25 healthy and 25 subjects with chronic periodontitis) was performed. DNA was isolated from peripheral blood of all the subjects and bisulfate modification with methylation specific polymerase chain reaction (MS-PCR) was performed. The methylation status of the selected region of the Tumor necrosis factor alpha gene for both the test and control groups was evaluated and assessed. The mean Ct value for the methylation of control group was 24.36 and in the periodontitis group the mean Ct value was found to be 28.09. The higher the Ct value, the lower is the amount of methylation observed. The periodontitis group had a higher mean Ct value as compared to the control group; indicating a lower amount of methylation in the promoter region of the periodontitis group as compared to the control group. A lower level of TNF alpha gene promoter (-239,-245) methylation was observed in the periodontitis group as compared to the controls and this observation appears to support a de-methylation of the TNF alpha promoter in the periodontitis subjects. Further studies evaluating the transcript levels of TNF alpha needs to be performed to confirm the observations of this study.

Investigation of Interleukin 1 Alpha Gene Promoter Polymorphism in Hemodialysis Patients with Arteriovenous Fistula Thrombosis

Investigation of Interleukin 1 Alpha Gene Promoter Polymorphism in Hemodialysis Patients with Arteriovenous Fistula Thrombosis

Choline Protects Against Intestinal Failure-Associated Liver Disease in Parenteral Nutrition-Fed Immature Rats.

Deficiency of choline, a required nutrient, is related to intestinal failure-associated liver disease (IFALD). Therefore, we aimed to investigate the effects of choline supplementation on IFALD and the underlying mechanisms. Male Sprague-Dawley rats (4 weeks old) were fed AIN-93G chow and administered intravenous 0.9% saline (control), parenteral nutrition (PN), or PN plus intravenous choline (600 mg/kg) for 7 days. We evaluated body weight, hepatic histology, biochemical indicators, triglycerides, oxidative status, methylation levels of peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, expression of PPARα and carnitine palmitoyltransferase 1 (CPT1), and levels of choline metabolites. The PN + choline group exhibited improved body weight compared with the PN group. PN impaired hepatic function, increased hepatic triglycerides, induced dyslipidemia, enhanced reactive oxygen species and malondialdehyde, and reduced total antioxidant capacity. The PN group had higher pathologic scores than the control group. These results were prevented by choline administration. Compared with the control group, PN increased PPARα promoter methylation and hepatic betaine concentration, reduced hepatic choline and phosphatidylcholine (PC) levels, decreased plasma choline and betaine concentrations, and downregulated PPARα and CPT1 mRNA and protein expression. Choline supplementation elevated hepatic choline and PC levels and enhanced plasma choline, betaine, and PC concentrations but reduced hepatic betaine level, reversed PPARα promoter hypermethylation, and upregulated PPARα and CPT1 mRNA and protein expression in PN-fed rats, compared with rats receiving PN alone. Choline addition to PN may prevent IFALD by reducing oxidative stress, enhancing hepatic fat export, and promoting fatty acid catabolism in immature rats receiving PN.

Tumor necrosis factor alpha polymorphisms are associated with Parkinson's disease age at onset.

The role of neuroinflammation in Parkinson's disease (PD) has been demonstrated through several different approaches. It was suggested an inflammation-derived oxidative stress and cytokine-dependent toxicity role in the nigrostriatal pathway degeneration and hasten progression of disease. Tumor necrosis factor alpha (TNFA) gene promoter polymorphisms might alter the expression of this cytokine contributing to the pro- and anti-inflammatory polarization. An increased TNFA expression might lead to inflammatory profile predominance. The aim of study was to determine if TNFA haplotypes are associated with PD age at onset. Five polymorphisms in TNFA gene were investigated in 226 patients with idiopathic PD in relation to age at onset. Haplotype grouping was based on allele expression. Logistic binary regression analysis showed that the genetic background leading to higher TNF-α expression confers a higher risk to develop PD earlier. Gender and ancestry did not differ between groups. High TNFA expression may contribute for faster dopaminergic neuron degeneration. In this context, a higher genetic pro-inflammatory profile confers a higher risk to develop PD earlier.

The association between acne vulgaris and Tumor Necrosis Factor- alpha gene promoter polymorphism at position-308

Background ;This study was carried out on (100) patients (64 females & 36 males) with different severity of acne vulgaris with an age range(11-40 )year, seen in AL-Diwaniya Teaching Hospital/ Department of Dermatology, from December 2011 to February 2012, another (50) apparently healthy subjects were taken as a control group. Materials; Blood samples were collected from both groups, genomic DNA was extracted from peripheral blood leukocytes for further molecular study, polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) technique was used .
 Results; genotyping of TNF-α revealed three genotypes; the wild homozygous GG type, the heterozygous GA & the mutant homozygous AA type, the genotype frequency for these three types in acne patients was (29%, 67% & 4%) respectively, in control group, however, it was (58%, 30% & 12%) respectively. The frequency for GA type was found statistically significantly increased in acne patients compared to the healthy controls (P<0.001), significant association was found between the minor A allele and females patients(40.6%) compared to healthy females(28.8%) ,P value 0.001,also all the female that had severe and very severe acne carry the GA genotype.

Tumor necrosis factor alpha gene promoter -238G/A polymorphism increases the risk of psoriasis vulgaris in Indian patients.

Tumor necrosis factor alpha (TNFα) gene -238G/A polymorphism (rs361525) is associated with psoriasis in several populations worldwide. To the best of our knowledge, there is no information about this polymorphism in Indian psoriatic patients. This study was undertaken to fill the gap in knowledge. This case-control study involved 72 patients with psoriasis vulgaris (PsV) and 72 age and gender matched healthy individuals. TNFα -238G/A polymorphism was genotyped by PCR-RFLP method. TNFα -238A allele was 5 times commoner in PsV patients than in the control group (P = 4.1 × 10-7 ; odds ratio [OR] = 6.5 [0.95 CI: 2.9-14.6]). Distribution of the genotypes in the two groups showed statistically significant difference in dominant genetic model (P = 2.3 × 10-7 ) and not in recessive genetic model (P = 2.5 × 10-1 ). Odds ratio for the occurrence of -238A genotype in PsV patients was 8.8 (0.95 CI: 3.5-20.2). The association showed no major difference when PsV patients were subgrouped into type I and type II categories and tested separately. Subgroup analysis on the basis of disease severity showed higher association with the moderate-severe subgroup (P = 2.4 × 10-9 , OR 15.4 [0.95 CI: 5.8-41.0]) than with mild subgroup (P = 1.3 × 10-2 , OR 3.8 [0.95 CI: 1.3-10.9]). Our results indicate that TNFα gene -238G/A polymorphism increases the risk of developing psoriasis vulgaris among Indians. Also, the data show that severity and not the type affects the strength of association in this population.

Association of −308G/A TNF-α gene polymorphism and spontaneous preterm birth in Acehnese ethnic group, Indonesia: This polymorphism is not associated with preterm birth

BackgroundSingle nucleotide polymorphism (SNP) within tumor necrosis factor alpha (TNF-α) gene promoter (−308G/A TNFA) is associated with higher gene expression. The role of this SNP as a risk factor for spontaneous preterm birth has been assessed in some regions and the findings were significantly different between race and ethnic groups. AimTo provide the scientific evidence whether allele A within SNP −308G/A TNFA promoter is a risk factor for spontaneous preterm birth among Acehnese ethnic or not. Subjects and methodsIn this case–control study, the genotypes of SNP −308G/A TNFA among 40 patients with spontaneous preterm birth and 40 patients with term birth were determined by real-time polymerase chain reaction (RT-PCR). The concentrations of TNF-α from blood were measured by enzyme-linked immunosorbent assay (ELISA). The differences in genotype distributions, dominant and recessive models, and allele frequencies between case and control groups were analyzed with Chi-squared test. Deviation of genotype frequencies from the Hardy–Weinberg equilibrium (HWE) was assessed by Fisher’s exact test. ResultsThis study found that the concentration of TNF-α between preterm and control groups was not statistically different, 5.5±2.9mg/dL vs. 10.1±17.9mg/dL, p=0.112. The level of TNF-α had no strong association with either genotype distribution or allele frequency of SNP −308G/A TNFA. Furthermore, there was no association between mutant genotypes and spontaneous preterm birth (OR: 0.32; 95%CI: 0.08–1.33, p=0.096) and between mutant allele and spontaneous preterm birth (OR: 0.35; 95%CI: 0.09–1.37, p=0.105). ConclusionSNP −308G/A TNFA is not associated with spontaneous preterm birth in Acehnese ethnic group.

Tumor necrosis factor alpha promoter polymorphism studies in pregnant women

AimsThe aim of this study was to explore the possible association between the −850C/T polymorphism in the tumor necrosis factor alpha (TNF-α) gene promoter, and pregnancy-associated diseases such as gestational diabetes mellitus (GDM) and preeclampsia (PE), in south Indian women. GDM and PE are common complications that occur during pregnancy and are the leading causes of perinatal mortality. To date, the mechanisms that initiate GDM and PE in humans have remained elusive. MethodsThis prospective case-control study was carried out with 505 pregnant women: 140 women had GDM, and 105 with PE. Remaining 260 women were age- and frequency-matched controls. TNF-α (–C850T) genotyping was determined by polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) analysis. ResultWe found no statistically significant difference in the genotypic and allelic distribution between GDM women and controls (for CT + TT vs. CC, χ2 = 0.3919; p = 0.61; Odds Ratio (OR) = 0.76 (95% CI: 0.203–1.876)). No significant differences was observed in the allele and genotype frequency between PE women and controls (for CT + TT vs. CC, p = 0.31; OR = 0.55 (95% CI: 0.171–1.784); T vs. C, p = 0.71; OR = 0.94 (95% CI: 0.680–1.3)). ConclusionFrom our results, we conclude that the (–C850T) promoter polymorphism has no role in the propensity of pregnant women from south Indian populations to develop GDM or PE.

Influence of tumor necrosis factor alpha gene promoter polymorphisms and its serum level on migraine susceptibility in Egyptian patients

BackgroundMigraine is a common chronic neurological disorder with still largely unknown pathogenesis. We aimed to explore the possible role of tumor necrosis factor alpha (TNF-α) gene polymorphisms as risk factors of migraine, and whether they influence the TNF-α level. Materials and methodsTwo hundred patients with migraine and 200 controls were enrolled in this study. Polymorphisms of TNF-α gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TNF-α level was measured using enzyme-linked immunosorbent assay (ELISA). ResultsTNF-α-308 GA, AA genotypes and A allele, TNF-α-857 CT genotype and T allele were associated with increased risk of migraine, while the TNF-α-238 polymorphism was not. TNF-α-308 GA, AA genotypes and A allele or AA genotype were associated with increased risk of migraine with aura (MA) and migraine without aura (MO) respectively; this was more significant in female patients with MA than in males. TNF-α-857 CT genotype was associated with increased risk of MO, or MA in females or males. While -857T allele was significantly associated with MO or MA in males and with MA only in females. On the other hand, we didn't find any significant associations of TNF-α-238 polymorphism with MO, or MA in males or females. TNF-α levels were higher in patients with migraine, MA, or MO than in controls (P<0.001). ConclusionTNF-α polymorphisms were associated with migraine, MA, or MO in Egyptians.

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM) on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic lipid metabolism, mitochondrial membrane potential (Δψm) and glutathione peroxidase (GSH-Px) in C3A cells exposed to excessive energy substrates (lactate, 10 mM; octanoate, 2 mM and pyruvate, 1 mM; lactate, octanoate and pyruvate-supplemented medium (LOP)). Thirty five micromole or 70 μM choline alone, instead of a low dose (5 μM), reduced hepatocellular triglyceride (TG) accumulation, protected Δψm from decrement and increased GSH-Px activity in C3A cells. The increment of TG accumulation, reactive oxygen species (ROS) production and Δψm disruption were observed under LOP treatment in C3A cells after 72 h of culture, which were counteracted by concomitant treatment of choline (35 μM or 70 μM) partially via reversing the methylation status of the peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, upregulating PPARα, carnitine palmitoyl transferase-I (CPT-I) and downregulating fatty acid synthase (FAS) gene expression, as well as decreasing FAS activity and increasing CPT-I and GSH-Px activities. These findings provided a novel insight into the lipotropic role of choline as a vital methyl-donor in the intervention of chronic metabolic diseases.

Liver X receptors alpha gene (NR1H3) promoter polymorphisms are associated with systemic lupus erythematosus in Koreans.

IntroductionLiver X receptors are established sensors of lipid and cholesterol homeostasis. Recent studies have reported that these receptors are involved in the regulation of inflammation and immune responses. We attempted to identify single nucleotide polymorphisms (SNPs) of the NR1H3 gene associated with the susceptibility to systemic lupus erythematosus (SLE).MethodsSNPs were genotyped using SNaPSHOT assay in 300 Korean patients with SLE and 217 normal controls (NC), and in replication samples (160 SLE patients and 143 NC). Also, the functional effects of NR1H3 gene promoter polymorphisms were analyzed using a luciferase assay, real-time polymerase chain reaction, B cell proliferation assay and an electrophoretic mobility shift assay.ResultsWe identified five polymorphisms: -1851 T > C (rs3758673), -1830 T > C (rs3758674), -1003 G > A (new), -840 C > A (rs61896015) and -115 G > A (rs12221497). There was a significant and reproducible difference in the -1830 T > C, -1003 G > A and -115 G > A polymorphisms between the SLE and the NC. Luciferase activity of the structure containing -1830 C was less enhanced compared to the structure containing -1830 T in basal, GW3965 and T0901317 treated Hep3B cells (P = 0.009, P = 0.034 and P <0.001, respectively). Proliferation of the -1830 TC type was increased compared to the -1830 TT type in basal, GW3965 and T0901317 treated B cells from SLE patients (P = 0.011, P = 0.040 and P = 0.017, respectively). Transcription factor GATA-3 preferentially bound the -1830 T allele in the promoter.ConclusionsNR1H3 genetic polymorphisms may be associated with disease susceptibility and clinical manifestations of SLE. Specifically, -1830 T > C polymorphism within NR1H3 promoter region may be involved in regulation of NR1H3 expression.

Study of association between promoter tumor necrosing factor alpha gene polymorphisms in -850T/C, -863 A/C, and endometriosis.

Background:The purpose of this study was to determine whether variability in gene encoding for promoter of tumor necrosis factor participates to women differences in susceptibility to endometriosis.Materials and Methods:The study involved 130 women; 65 endometriotic and 65 healthy control women. The blood samples were genotyped for -850 T/C and -863 C/A polymorphisms in TNF alpha gene promoter. Chi-square, odd ratio, and confidence interval 95% were used to evaluate genotypes and allele frequency differences between two groups.Results:No significant differences in genotypes distribution of -850 T/C (P = 0.32) and 863 C/A (P = 0.34) polymorphisms were obtained between two groups.Conclusion:According to this study, these two polymorphisms have no risk or protective factor to develop endometriosis.

Determination of the Cytokine Gene Polymorphism and Genetic Susceptibility in Tuberculosis Patients

Tuberculosis (TB) is a complicated disease in which biological, socioeconomical and environmental factors play role. Since only 10% of the individuals infected with Mycobacterium tuberculosis develop active disease, it has been suggested that host genetic factors may influence the risk for the development of TB. In this study, we aimed to investigate the presence and role of single nucleotide polymorphisms in the gene regions responsible for cytokine production, since these factors are considered to be associated with susceptibility or resistance to disease development. Single nucleotide polymorphisms were investigated by Amplification Refractory Mutational System (ARMS) Polymerase Chain Reaction (PCR) and PCR-Restriction Fragment Length Polymorphism (RFLP) methods. The presence of single nucleotide polymorphisms were analyzed in tumor necrosis factor alpha (TNF-α) gene promoter -308 G>A (rs1800629) region, interferon gamma (IFN-γ) gene +874 T>A (rs61923114) region, interleukin (IL)-12B p40 gene 1188 A>C (rs3212227) region, IL-10 gene promoter -1082 G>A (rs1800896) region and IL-4 gene promoter -590 C>T (rs2243250) region. A total of 84 patients (71 male, 13 female; mean age: 32.57 ± 15.94 years) whose clinical samples yielded M.tuberculosis complex growth, and 110 healthy blood donors (93 male, 17 female; mean age: 29.40 ± 11.56 years) as control group were included in this study. Of the patients, 76 (90.5%) were diagnosed as pulmonary and 8 (9.5%) as extrapulmonary TB. While 79 (94.1%) patients were newly diagnosed as TB, 5 (5.9%) patients had a TB history (relapsed TB). It was detected that acid-fast bacilli (AFB) were positive in 58 (69%) patients. According to the single nucleotide polymorphism results, gene frequencies could not be compared for TNF-a gene promoter -308 G>A region since healthy controls were in Hardy-Weinberg equilibrium while the patients were not. There were no statistically significant differences in allele and genotype distribution between the patients and healthy controls in IFN-γ gene +874 T>A region, IL-12B p40 gene 1188 A>C region, IL-10 gene promoter -1082 G>A region and IL-4 gene promoter -590 C>T region (p> 0.05). There were also no statistically significant differences between AFB positive (n= 58) and negative (n= 26) patients, and AFB positive (n= 56) and negative (n= 20) pulmonary TB patients (p> 0.05). In conclusion, no statistically significant differences were found associated with the susceptibility or resistance to TB with single nucleotide polymorphisms in the gene regions responsible for cytokine production in the study population. Only some of the single nucleotide polymorphisms of the gene regions responsible for cytokine release were investigated in our study. Therefore further detailed studies to investigate the polymorphisms in the genes that control the cytokine release and receptors specific for these cytokines, should be conducted. Although this study was performed in a relatively small sized population, these findings might provide a significant contribution to the epidemiologic data about the molecular immunology of TB in Turkey.

Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke

BackgroundTumor necrosis factor-α (TNF-α) is one of the most typical pro-inflammatory cytokines with both beneficial and destructive properties for the central nervous system. Increasing evidences have demonstrated the important role of TNF-α in the development of ischemic stroke, but studies examining the possible association with stroke or direct functional effects of polymorphisms in TNF-α have been contradictory.FindingsIn this study, a 2-kb length of the proximal promoter of the TNF-α was screened and four polymorphisms were investigated in the case–control study. Our data confirmed the association between -308G/A variant with stroke in 1,388 stroke patients and 1,027 controls and replicated in an independent population of 961 stroke patients and 821 controls (odds ratio (OR) = 1.34, 95% confidence interval (CI) =1.02 to 1.77 and OR = 1.56, 95% CI = 1.09 to 2.23, respectively). To reconcile the association between polymorphisms and stroke and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 15 published studies in an Asian population. Our results demonstrated an association between rs1800629 and ischemic stroke (OR = 1.43, 95% CI = 1.21 to 1.69). Another meta-analysis results of 14 studies demonstrated that ischemic stroke patients have higher serum TNF-α level than the control subjects (standardized mean difference (SMD) = 2.33, 95% CI = 1.85 to 2.81). In vitro evaluation of potential interaction between variants of the TNF-α gene (−308G/A, -857C/T, and -1031T/C) demonstrated that these three polymorphisms could interact together to determine the overall activity of the TNF-α gene.ConclusionsThese findings strongly implicate the involvement of TNF-α in the pathogenesis of stroke.

DNA methylation and hepatic insulin resistance and steatosis

In this review, we show novel evidence about the role of the liver in the development of insulin resistance and suggest that abnormal hepatic triglyceride accumulation is not an innocent bystander comorbidity but adversely affects the peripheral insulin sensitivity. The core of this review is built up around the concept that liver DNA methylation of the peroxisome proliferative activated receptor gamma coactivator one alpha gene promoter modulates the status of peripheral insulin resistance and is strongly associated with plasma fasting insulin levels. We discuss about other mechanisms associated with peroxisome proliferative activated receptor gamma coactivator one alpha regulation, such as an acetylation and deacetylation switch and how these events impact on the liver metabolic function. We suggest a mitochondrial-centric approach to understand the connection between nonalcoholic fatty liver disease and insulin resistance. We finally show new data about how the liver epigenome is modulated by nutritional cues and introduce the role of epigenetics in liver metabolic programming. The implications of these findings for clinical practice are promising, as the inherent plasticity of epigenetic modifications, produced either physiologically or pathologically, suggests that early therapeutic intervention in patients with fatty liver can potentially revert the systemic phenotype associated with insulin resistance.

Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter

Human estrogen receptors alpha and beta are crucially involved in the regulation of mammary growth and development. Normal breast tissues display a relative higher expression of ER beta than ER alpha, which drastically changes during breast tumorogenesis. Thus, it is reasonable to suggest that a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanisms underlying the potential opposing roles played by the two estrogen receptors on tumor cell growth remain to be elucidated. In the present study, we have demonstrated that ER beta overexpression in breast cancer cells decreases cell proliferation and down-regulates ER alpha mRNA and protein content, along with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ER alpha promoter region, showed that elevated levels of ER beta down-regulated basal ER alpha promoter activity. Furthermore, site-directed mutagenesis and deletion analysis revealed that the proximal GC-rich motifs at -223 and -214 are critical for the ER beta-induced ER alpha down-regulation in breast cancer cells. This occurred through ER beta-Sp1 protein-protein interactions within the ER alpha promoter region and the recruitment of a corepressor complex containing the nuclear receptor corepressor NCoR, accompanied by hypoacetylation of histone H4 and displacement of RNA-polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effects of ER beta on ER alpha gene expression and cell proliferation. Our results provide evidence for a novel mechanism by which overexpression of ER beta through NCoR is able to down regulate ER alpha gene expression, thus blocking ER alpha's driving role on breast cancer cell growth.

Thyroglobulin gene is associated with premature ovarian failure

Variants of the thyroglobulin gene were significantly associated with premature ovarian failure in a Korean population. Three single nucleotide polymorphisms and one haplotype were found to be associated with a significant increase in the risk for premature ovarian failure.