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induced cell death is counteracted by NF-κB-mediated transcription of DARPP-32.
Zhu S, Soutto M, Chen Z, Peng D, Romero-Gallo J, Krishna US, Belkhiri A, Washington MK, Peek R, El-Rifai W
(2017) Gut 66: 761-762
MeSH Terms: Animals, Cell Death, Cell Line, Tumor, Cell Survival, Dopamine and cAMP-Regulated Phosphoprotein 32, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Mice, NF-kappa B, Promoter Regions, Genetic, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, Stomach Neoplasms, Transcription, Genetic, Tumor Necrosis Factor-alpha
Show Abstract · Added April 6, 2017
OBJECTIVE - is a frequently amplified and overexpressed gene that promotes several oncogenic functions in gastric cancer. Herein, we investigated the relationship between infection, proinflammatory NF-κB activation and regulation of DARPP-32.
DESIGN - The study used and experiments. Luciferase reporter, quantitative real-time PCR, immunoblot, chromatin immunoprecipitation (ChIP), cell viability, infection, tissue microarrays and immunohistochemical assays were used.
RESULTS - Our results indicated that infection increased the DARPP-32 mRNA and protein levels in gastric cancer cell lines and gastric mucosa of mice. infection increased the activity of NF-κB reporter and p-NF-κB (S536) protein level and . To investigate the transcriptional regulation of DARPP-32, we cloned a 3019 bp of the promoter into the luciferase reporter (pGL3-Luc). Both infection and tumour necrosis factor-α treatment induced DARPP-32 reporter activity (p<0.01). Using deletion constructs of promoter and ChIP assay, we demonstrated that the sequence -996 to -1008 bp containing putative NF-κB-binding sites is the most active region. The induction of DARPP-32 expression by infection counteracted -induced cell death through activation of serine/threonine-specific protein kinase (AKT), as determined by ATP-Glo and clonogenic survival assays. Immunohistochemistry analysis demonstrated a significant positive correlation between NF-κB and DARPP-32 expression levels in gastric cancer tissues (r=0.43, p<0.01).
CONCLUSIONS - Given the high frequency of DARPP-32 overexpression and its prosurvival oncogenic functions, the induction of DARPP-32 expression following infection and activation of NF-κB provides a link between infection, inflammation and gastric tumourigenesis.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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18 MeSH Terms
High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
(2016) Cell Rep 16: 2003-16
MeSH Terms: Antineoplastic Agents, Azepines, Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Directed RNA Polymerases, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Multigene Family, Myeloid Cell Leukemia Sequence 1 Protein, Promoter Regions, Genetic, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-kit, Transcription, Genetic, Translocation, Genetic, Triazoles
Show Abstract · Added April 6, 2017
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.
Zeng C, Guo X, Long J, Kuchenbaecker KB, Droit A, Michailidou K, Ghoussaini M, Kar S, Freeman A, Hopper JL, Milne RL, Bolla MK, Wang Q, Dennis J, Agata S, Ahmed S, Aittomäki K, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Arun BK, Arver B, Bacot F, Barrowdale D, Baynes C, Beeghly-Fadiel A, Benitez J, Bermisheva M, Blomqvist C, Blot WJ, Bogdanova NV, Bojesen SE, Bonanni B, Borresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Broeks A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldes T, Campbell I, Carpenter J, Chang-Claude J, Choi JY, Claes KB, Clarke C, Cox A, Cross SS, Czene K, Daly MB, de la Hoya M, De Leeneer K, Devilee P, Diez O, Domchek SM, Doody M, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dumont M, Dwek M, Dworniczak B, Egan K, Eilber U, Einbeigi Z, Ejlertsen B, Ellis S, Frost D, Lalloo F, EMBRACE, Fasching PA, Figueroa J, Flyger H, Friedlander M, Friedman E, Gambino G, Gao YT, Garber J, García-Closas M, Gehrig A, Damiola F, Lesueur F, Mazoyer S, Stoppa-Lyonnet D, behalf of GEMO Study Collaborators, Giles GG, Godwin AK, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Haiman CA, Hallberg E, Hamann U, Hansen TV, Hart S, Hartikainen JM, Hartman M, Hassan N, Healey S, Hogervorst FB, Verhoef S, HEBON, Hendricks CB, Hillemanns P, Hollestelle A, Hulick PJ, Hunter DJ, Imyanitov EN, Isaacs C, Ito H, Jakubowska A, Janavicius R, Jaworska-Bieniek K, Jensen UB, John EM, Joly Beauparlant C, Jones M, Kabisch M, Kang D, Karlan BY, Kauppila S, Kerin MJ, Khan S, Khusnutdinova E, Knight JA, Konstantopoulou I, Kraft P, Kwong A, Laitman Y, Lambrechts D, Lazaro C, Le Marchand L, Lee CN, Lee MH, Lester J, Li J, Liljegren A, Lindblom A, Lophatananon A, Lubinski J, Mai PL, Mannermaa A, Manoukian S, Margolin S, Marme F, Matsuo K, McGuffog L, Meindl A, Menegaux F, Montagna M, Muir K, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Newcomb PA, Nord S, Nussbaum RL, Offit K, Olah E, Olopade OI, Olswold C, Osorio A, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Peeters S, Peissel B, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Presneau N, Radice P, Rahman N, Ramus SJ, Rashid MU, Rennert G, Rhiem K, Rudolph A, Salani R, Sangrajrang S, Sawyer EJ, Schmidt MK, Schmutzler RK, Schoemaker MJ, Schürmann P, Seynaeve C, Shen CY, Shrubsole MJ, Shu XO, Sigurdson A, Singer CF, Slager S, Soucy P, Southey M, Steinemann D, Swerdlow A, Szabo CI, Tchatchou S, Teixeira MR, Teo SH, Terry MB, Tessier DC, Teulé A, Thomassen M, Tihomirova L, Tischkowitz M, Toland AE, Tung N, Turnbull C, van den Ouweland AM, van Rensburg EJ, Ven den Berg D, Vijai J, Wang-Gohrke S, Weitzel JN, Whittemore AS, Winqvist R, Wong TY, Wu AH, Yannoukakos D, Yu JC, Pharoah PD, Hall P, Chenevix-Trench G, KConFab, AOCS Investigators, Dunning AM, Simard J, Couch FJ, Antoniou AC, Easton DF, Zheng W
(2016) Breast Cancer Res 18: 64
MeSH Terms: Alleles, BRCA1 Protein, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 12, Computational Biology, Databases, Genetic, Enhancer Elements, Genetic, Epigenesis, Genetic, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Heterozygote, Humans, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Population Surveillance, Promoter Regions, Genetic, Quantitative Trait Loci, Risk
Show Abstract · Added April 18, 2017
BACKGROUND - Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
METHOD - We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.
RESULTS - Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.
CONCLUSION - This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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25 MeSH Terms
G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress.
Boortz KA, Syring KE, Dai C, Pound LD, Oeser JK, Jacobson DA, Wang JC, McGuinness OP, Powers AC, O'Brien RM
(2016) Endocrinology 157: 3002-8
MeSH Terms: Animals, Blood Glucose, Cells, Cultured, Dexamethasone, Fasting, Gene Expression Regulation, Glucose-6-Phosphatase, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreas, Promoter Regions, Genetic, Stress, Physiological
Show Abstract · Added July 16, 2016
The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress.
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15 MeSH Terms
Epigenetic and genetic variation in GATA5 is associated with gastric disease risk.
Sobota RS, Kodaman N, Mera R, Piazuelo MB, Bravo LE, Pazos A, Zabaleta J, Delgado AG, El-Rifai W, Morgan DR, Wilson KT, Correa P, Williams SM, Schneider BG
(2016) Hum Genet 135: 895-906
MeSH Terms: Adult, DNA Methylation, Epigenomics, Female, GATA5 Transcription Factor, Genetic Association Studies, Genotype, Helicobacter Infections, Helicobacter pylori, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Stomach Neoplasms
Show Abstract · Added May 28, 2016
Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were β = -0.863 and β = -0.815, respectively, where β is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (β = -0.256, 95 % CI = -0.47, -0.039; and β = -0.239, 95 % CI = -0.45, -0.024), and rs6587239 was significantly associated in a dominant-effects model (β = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other.
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16 MeSH Terms
BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.
Chen J, Wang Z, Hu X, Chen R, Romero-Gallo J, Peek RM, Chen LF
(2016) J Immunol 196: 4132-42
MeSH Terms: Azepines, Cell Line, Tumor, Enhancer Elements, Genetic, Gastritis, Gene Expression Regulation, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation Mediators, NF-kappa B, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, RNA, Messenger, Transcription Factors, Triazoles
Show Abstract · Added April 6, 2017
Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer.
Copyright © 2016 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.
Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, Anjum S, Wang J, Manyam G, Zoppoli P, Ling S, Rao AA, Grifford M, Cherniack AD, Zhang H, Poisson L, Carlotti CG, Tirapelli DP, Rao A, Mikkelsen T, Lau CC, Yung WK, Rabadan R, Huse J, Brat DJ, Lehman NL, Barnholtz-Sloan JS, Zheng S, Hess K, Rao G, Meyerson M, Beroukhim R, Cooper L, Akbani R, Wrensch M, Haussler D, Aldape KD, Laird PW, Gutmann DH, TCGA Research Network, Noushmehr H, Iavarone A, Verhaak RG
(2016) Cell 164: 550-63
MeSH Terms: Adult, Brain Neoplasms, Cell Proliferation, Cluster Analysis, DNA Helicases, DNA Methylation, Epigenesis, Genetic, Glioma, Humans, Isocitrate Dehydrogenase, Middle Aged, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Signal Transduction, Telomerase, Telomere, Transcriptome, X-linked Nuclear Protein
Show Abstract · Added August 8, 2016
Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
Copyright © 2016 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.
Ma Y, Follis JL, Smith CE, Tanaka T, Manichaikul AW, Chu AY, Samieri C, Zhou X, Guan W, Wang L, Biggs ML, Chen YD, Hernandez DG, Borecki I, Chasman DI, Rich SS, Ferrucci L, Irvin MR, Aslibekyan S, Zhi D, Tiwari HK, Claas SA, Sha J, Kabagambe EK, Lai CQ, Parnell LD, Lee YC, Amouyel P, Lambert JC, Psaty BM, King IB, Mozaffarian D, McKnight B, Bandinelli S, Tsai MY, Ridker PM, Ding J, Mstat KL, Liu Y, Sotoodehnia N, Barberger-Gateau P, Steffen LM, Siscovick DS, Absher D, Arnett DK, Ordovás JM, Lemaitre RN
(2016) Am J Clin Nutr 103: 567-78
MeSH Terms: ATP Binding Cassette Transporter 1, Apolipoproteins E, Cholesterol, HDL, Cohort Studies, DNA Methylation, Diet, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides
Show Abstract · Added February 18, 2016
BACKGROUND - DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.
OBJECTIVE - We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.
DESIGN - We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.
RESULTS - On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).
CONCLUSION - We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.
© 2016 American Society for Nutrition.
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15 MeSH Terms
The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter.
Ma Y, Smith CE, Lai CQ, Irvin MR, Parnell LD, Lee YC, Pham LD, Aslibekyan S, Claas SA, Tsai MY, Borecki IB, Kabagambe EK, Ordovás JM, Absher DM, Arnett DK
(2016) Mol Nutr Food Res 60: 410-9
MeSH Terms: Adult, CpG Islands, DNA Methylation, Fatty Acids, Omega-3, Female, Humans, Interleukin-6, Male, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
Show Abstract · Added February 18, 2016
SCOPE - Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6.
METHODS AND RESULTS - Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (p = 0.03) and greater IL6 gene expression (p = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p = 0.007) and lower IL-6 concentration (p = 0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p = 2.55 × 10(-7) ). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p = 0.04) not in the homozygotes.
CONCLUSION - Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms
Novel BAC Mouse Model of Huntington's Disease with 225 CAG Repeats Exhibits an Early Widespread and Stable Degenerative Phenotype.
Wegrzynowicz M, Bichell TJ, Soares BD, Loth MK, McGlothan JS, Mori S, Alikhan FS, Hua K, Coughlin JM, Holt HK, Jetter CS, Pomper MG, Osmand AP, Guilarte TR, Bowman AB
(2015) J Huntingtons Dis 4: 17-36
MeSH Terms: Animals, Atrophy, Behavior, Animal, Brain, Chromosomes, Artificial, Bacterial, Disease Models, Animal, Disease Progression, Huntington Disease, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phenotype, Promoter Regions, Genetic, Serotonin Plasma Membrane Transport Proteins, Trinucleotide Repeat Expansion
Show Abstract · Added February 15, 2016
BACKGROUND - Unusually large CAG repeat expansions (>60) in exon one of Huntingtin (HTT) are invariably associated with a juvenile-onset form of Huntington's disease (HD), characterized by a more extensive and rapidly progressing neuropathology than the more prevalent adult-onset form. However, existing mouse models of HD that express the full-length Htt gene with CAG repeat lengths associated with juvenile HD (ranging between ~75 to ~150 repeats in published models) exhibit selective neurodegenerative phenotypes more consistent with adult-onset HD. Objective: To determine if a very large CAG repeat (>200) in full-length Htt elicits neurodegenerative phenotypes consistent with juvenile HD.
METHODS - Using a …bacterial artificial chromosome (BAC) system, we generated mice expressing full-length mouse Htt with ~225 CAG repeats under control of the mouse Htt promoter. Mice were characterized using behavioral, neuropathological, biochemical and brain imaging methods.
RESULTS - BAC-225Q mice exhibit phenotypes consistent with a subset of features seen in juvenile-onset HD: very early motor behavior abnormalities, reduced body weight, widespread and progressive increase in Htt aggregates, gliosis, and neurodegeneration. Early striatal pathology was observed, including reactive gliosis and loss of dopamine receptors, prior to detectable volume loss. HD-related blood markers of impaired energy metabolism and systemic inflammation were also increased. Aside from an age-dependent progression of diffuse nuclear aggregates at 6 months of age to abundant neuropil aggregates at 12 months of age, other pathological and motor phenotypes showed little to no progression.
CONCLUSIONS - The HD phenotypes present in animals 3 to 12 months of age make the BAC-225Q mice a unique and stable model of full-length mutant Htt associated phenotypes, including body weight loss, behavioral impairment and HD-like neurodegenerative phenotypes characteristic of juvenile-onset HD and/or late-stage adult-onset HD.
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16 MeSH Terms