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1.
Nat Commun ; 10(1): 4957, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673082

RESUMO

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

2.
Proc Natl Acad Sci U S A ; 116(38): 19064-19070, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31481615

RESUMO

Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data for 2,554 individuals from across the entire archipelago with geographically restricted ancestry, and performed population structure analyses and comparisons to ancient DNA. Extensive geographic structuring is revealed, from broad scales such as a NE to SW divide in mainland Scotland, through to the finest scale observed to date: across 3 km in the Northern Isles. Many genetic boundaries are consistent with Dark Age kingdoms of Gaels, Picts, Britons, and Norse. Populations in the Hebrides, the Highlands, Argyll, Donegal, and the Isle of Man show characteristics of isolation. We document a pole of Norwegian ancestry in the north of the archipelago (reaching 23 to 28% in Shetland) which complements previously described poles of Germanic ancestry in the east, and "Celtic" to the west. This modern genetic structure suggests a northwestern British or Irish source population for the ancient Gaels that contributed to the founding of Iceland. As rarer variants, often with larger effect sizes, become the focus of complex trait genetics, more diverse rural cohorts may be required to optimize discoveries in British and Irish populations and their considerable global diaspora.

3.
Nat Commun ; 10(1): 2069, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043600

RESUMO

In the original version of this Article, the legend in the upper panel of Figure 2 incorrectly read 'paternal imprinting' and should have read 'maternal imprinting'. This has been corrected in both the PDF and HTML versions of the Article.

4.
Nat Commun ; 10(1): 1383, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918249

RESUMO

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.


Assuntos
Metilação de DNA/genética , Regulação da Expressão Gênica , Impressão Genômica/genética , Locos de Características Quantitativas/genética , Adulto , Ilhas de CpG , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escócia
5.
Nat Genet ; 51(2): 245-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643258

RESUMO

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.


Assuntos
Comportamento/fisiologia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudos de Casos e Controles , Feminino , Genética Comportamental/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
6.
Elife ; 82019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642433

RESUMO

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

7.
Artigo em Inglês | MEDLINE | ID: mdl-30216705

RESUMO

BACKGROUND: Inconsistencies in the nomenclature of structures of the frontal sinus have impeded the development of a validated "reference standard" classification system that surgeons can reliably agree upon. The International Frontal Sinus Anatomy Classification (IFAC) system was developed as a consensus document, based on expert opinion, attempting to address this issue. The purposes of this study are to: establish the reliability of the IFAC as a tool for classifying cells in the frontal recess among an international group of rhinologists; and improve communication and teaching of frontal endoscopic sinus surgery (ESS). METHODS: Forty-two computed tomography (CT) scans, each with a marked frontal cell, were reviewed by 15 international fellowship-trained rhinologists. Each marked cell was classified into 1 of 7 categories described in the IFAC, on 2 occasions separated by 2 weeks. Inter- and intrarater reliability were evaluated using Light's kappa (κ), the interclass correlation coefficient (ICC), and simple proportion of agreement. RESULTS: Interrater reliability showed pairwise κ values ranging from 0.7248 to 1.0, with a mean of 0.9162 (SD, 0.0537). The ICC was 0.98. Intrarater reliability showed κ values ranging from 0.8613 to 1.0, with a mean of 0.9407 (SD, 0.0376). The within-rater ICC was 0.98. CONCLUSION: Among a diverse sample of rhinologists (raters), there was substantial to almost perfect agreement between raters, and among individual raters at different timepoints. The IFAC is a reliable tool for classification of cells in the frontal sinus. Further outcome studies are still needed to determine the validity of the IFAC.

8.
Ear Nose Throat J ; 97(6): 173-176, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30036414

RESUMO

Surgical treatments for nasal airway obstruction (NAO) are commonly offered as part of otolaryngology practice. Anatomic causes include septal deviation, inferior turbinate hypertrophy, and nasal valve collapse (NVC). This study was performed to determine the prevalence of anatomic contributors to NAO. A total of 1,906 patients with sinonasal complaints were surveyed by 50 otolaryngologists in varying U.S. geographic regions. Patients were first evaluated using the Nasal Obstruction Symptom Evaluation (NOSE) instrument to assess the NAO symptoms and their severity. Physicians then examined patients for the presence of the three anatomic contributors. Presence of septal deviation and turbinate hypertrophy was assessed through an internal nasal exam with direct or endoscopic visualization based on the physician's standard methodology for diagnosis. Presence of NVC was determined by the modified Cottle maneuver. Among all patients surveyed, prevalence was 67% for NVC, 76% for septal deviation, and 72% for inferior turbinate hypertrophy. We found that 64% of the patients (n = 1,211) had severe/extreme NOSE scores (≥55), representing the most likely nasal obstruction candidates for intervention. In these patients, the prevalence of NVC, septal deviation, and inferior turbinate hypertrophy was 73, 80, and 77%, respectively. Eighty-two percent of the 236 patients with severe/extreme NOSE scores who reported prior septoplasty and/or inferior turbinate reduction had NVC. Our study revealed a comparable prevalence of all three anatomic contributors across all patients and the subset with severe/extreme NOSE scores, highlighting the importance of evaluating the lateral nasal wall as a component of NAO treatment strategy.


Assuntos
Cavidade Nasal/anormalidades , Obstrução Nasal/etiologia , Deformidades Adquiridas Nasais/epidemiologia , Índice de Gravidade de Doença , Conchas Nasais/patologia , Endoscopia , Feminino , Humanos , Hipertrofia/epidemiologia , Masculino , Obstrução Nasal/diagnóstico , Obstrução Nasal/epidemiologia , Septo Nasal/patologia , Deformidades Adquiridas Nasais/complicações , Otolaringologia/estatística & dados numéricos , Prevalência , Inquéritos e Questionários , Estados Unidos/epidemiologia
9.
Nat Genet ; 50(8): 1112-1121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038396

RESUMO

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

10.
Mol Cell Oncol ; 5(1): e1392403, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29404391

RESUMO

Mortality in ovarian cancer is predominantly due to acquired chemoresistance and tumor recurrence. UBIQUITIN CONJUGATING ENZYME E2 or RAD6 expression increases in cell lines and patient tumors in response to platinum-based chemotherapy and promotes both activation of DNA damage response pathways and expression of stemness genes and a stem cell-like phenotype driving ovarian cancer chemoresistance.

11.
Nat Rev Genet ; 19(4): 220-234, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29335644

RESUMO

Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.

12.
Nat Commun ; 8(1): 910, 2017 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-29030599

RESUMO

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.


Assuntos
Cadeias alfa de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Estilo de Vida , Lipoproteína(a)/genética , Longevidade/genética , Alelos , Índice de Massa Corporal , Doença das Coronárias/sangue , Doença das Coronárias/etiologia , Educação , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina/genética , Lipoproteínas HDL/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Fatores Socioeconômicos
13.
Proc (Bayl Univ Med Cent) ; 30(4): 457-458, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28966465

RESUMO

Inverted papilloma of the nasal cavity is a benign neoplasm, although it can be locally invasive and has the potential for malignant degeneration. Inverted papilloma of the temporal bone is extremely rare. We describe a case of a 44-year-old woman who was treated for nasal inverted papilloma and was later found to have inverted papilloma of her temporal bone. The patient required several procedures to remove the inverted papilloma from the nasal cavity and temporal bone, and she is currently free of recurrence.

14.
Proc (Bayl Univ Med Cent) ; 30(4): 461-462, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28966467

RESUMO

A deep neck abscess is uncommon in the newborn period. In this case, we noted a clindamycin-sensitive methicillin-resistant Staphylococcus aureus infection characterized as a deep neck abscess in an 8-day-old boy. He was admitted to the pediatric intensive care unit with a progressively enlarging indurated mass below the mandible. Imaging confirmed the mass as a submandibular abscess. The patient received antibiotics in addition to incision and drainage, with resolution of the abscess.

15.
Proc (Bayl Univ Med Cent) ; 30(2): 221-223, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28405090

RESUMO

A respiratory epithelial adenomatoid hamartoma (REAH) is an uncommon benign lesion often found in the sinonasal tract. We present a case of bilateral REAH originating from the anterior olfactory cleft treated with endoscopic surgical resection without recurrence. We highlight the characteristics of REAH and necessary steps to ensure proper diagnosis and treatment.

16.
Mol Carcinog ; 56(3): 1010-1020, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27597267

RESUMO

The normal female reproductive hormone estrogen has been linked with increased risk of breast and many other forms of cancer. This is largely due to metabolic conversion of estrogens into highly reactive catechol estrogen quinones which can interact with DNA and cause a variety of DNA adducts and lesions. Detection and analysis of these adducts and their associated cellular responses involve complex chemical, enzymatic, and LC-MS based methods, which are both laborious and require specialized expertise and instrumentation. Herein, we show that using a biotin-labeled estradiol allows immunodetection of estrogen-induced DNA adducts by slot blot and single-cell molecular combing and proximity ligation assays. The biotinylated and unlabeled estradiols induced similar levels of DNA single and double strand breaks as measured by comet assays. Using biotinylated estrogen, we further show that estrogens are able to activate the Fanconi anemia-BRCA tumor suppressor pathway and cause DNA strand breaks and oxidatively modified DNA bases as well as gross chromosomal aberrations. Utilization of biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and associated DNA damage, and to track estrogen adduct-induced cellular responses and carcinogenic mechanisms in cultured cells. The techniques presented here allow simple and rapid detection and quantitation of estrogen adducts by slot blot as well as direct visualization on the DNA strand and could pave the way for developing new treatments to protect the genome from the effects of reactive estrogen metabolites. © 2016 Wiley Periodicals, Inc.


Assuntos
Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Estradiol/química , Estrogênios/toxicidade , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Biotinilação , Células Cultivadas , Aberrações Cromossômicas , Estrogênios/química , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Análise de Célula Única
17.
Oncotarget ; 7(11): 12537-53, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26871286

RESUMO

Camptothecin (CPT) and its analogues are chemotherapeutic agents that covalently and reversibly link DNA Topoisomerase I to its nicked DNA intermediate eliciting the formation of DNA double strand breaks (DSB) during replication. The repair of these DSB involves multiple DNA damage response and repair proteins. Here we demonstrate that CPT-induced DNA damage promotes functional interactions between BRCA2, FANCD2, Rad18, and Rad51 to repair the replication-associated DSB through homologous recombination (HR). Loss of any of these proteins leads to equal disruption of HR repair, causes chromosomal aberrations and sensitizes cells to CPT. Rad18 appears to function upstream in this repair pathway as its downregulation prevents activation of FANCD2, diminishes BRCA2 and Rad51 protein levels, formation of nuclear foci of all three proteins and recovery of stalled or collapsed replication forks in response to CPT. Taken together this work further elucidates the complex interplay of DNA repair proteins in the repair of replication-associated DSB.


Assuntos
Camptotecina/farmacologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Rad51 Recombinase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Células HCT116 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , RNA Interferente Pequeno/metabolismo , Transfecção , Ubiquitina-Proteína Ligases/genética
18.
Ann Transl Med ; 4(24): 518, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28149880

RESUMO

Resistance to current chemotherapeutic or radiation-based cancer treatment strategies is a serious concern. Cancer stem cells (CSCs) are typically able to evade treatment and establish a recurrent tumor or metastasis, and it is these that lead to the majority of cancer deaths. Therefore, a major current goal is to develop treatment strategies that eliminate the resistant CSCs as well as the bulk tumor cells in order to achieve complete disease clearance. Aldehyde dehydrogenases (ALDHs) are important for maintenance and differentiation of stem cells as well as normal development. There is expanding evidence that ALDH expression increases in response to therapy and promotes chemoresistance and survival mechanisms in CSCs. This perspective will discuss a paper by Cojoc and colleagues recently published in Cancer Research, that indicates ALDHs play a key role in resistance to radiation therapy and tumor recurrence in prostate cancer. The authors suggest that ALDHs are a potential therapeutic target for treatment prostate cancer patients to limit radiation resistance and disease recurrence. The findings are consistent with work from other cancers showing ALDHs are major contributors of CSC signaling and resistance to anti-cancer treatments. This perspective will address representative work concerning the validity of ALDH and the associated retinoic acid signaling pathway as chemotherapeutic targets for prostate as well as other cancers.

19.
Biochem Biophys Res Commun ; 469(3): 449-55, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26679603

RESUMO

Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression. Furthermore, in ovarian cancer cells Rad6 was found to stabilize ß-catenin promoting stem cell-related characteristics, including expression of stem cell markers and anchorage-independent growth. Cancer stem cells can promote chemoresistance, tumor recurrence and metastasis, all of which are limiting factors in treating ovarian cancer. Thus it is significant that Rad6 overexpression led to increased resistance to the chemotherapeutic drug carboplatin and correlated with tumor cell invasion. These findings show the importance of Rad6 in ovarian cancer and emphasize the need for further studies of Rad6 as a potential target for the treatment of ovarian cancer.


Assuntos
Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Compostos de Platina/administração & dosagem , Enzimas de Conjugação de Ubiquitina/metabolismo , Antineoplásicos/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Regulação para Cima/efeitos dos fármacos
20.
Am J Physiol Lung Cell Mol Physiol ; 309(11): L1367-75, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26432868

RESUMO

In hypoxia, mitochondria-generated reactive oxygen species not only stimulate accumulation of the transcriptional regulator of hypoxic gene expression, hypoxia inducible factor-1 (Hif-1), but also cause oxidative base modifications in hypoxic response elements (HREs) of hypoxia-inducible genes. When the hypoxia-induced base modifications are suppressed, Hif-1 fails to associate with the HRE of the VEGF promoter, and VEGF mRNA accumulation is blunted. The mechanism linking base modifications to transcription is unknown. Here we determined whether recruitment of base excision DNA repair (BER) enzymes in response to hypoxia-induced promoter modifications was required for transcription complex assembly and VEGF mRNA expression. Using chromatin immunoprecipitation analyses in pulmonary artery endothelial cells, we found that hypoxia-mediated formation of the base oxidation product 8-oxoguanine (8-oxoG) in VEGF HREs was temporally associated with binding of Hif-1α and the BER enzymes 8-oxoguanine glycosylase 1 (Ogg1) and redox effector factor-1 (Ref-1)/apurinic/apyrimidinic endonuclease 1 (Ape1) and introduction of DNA strand breaks. Hif-1α colocalized with HRE sequences harboring Ref-1/Ape1, but not Ogg1. Inhibition of BER by small interfering RNA-mediated reduction in Ogg1 augmented hypoxia-induced 8-oxoG accumulation and attenuated Hif-1α and Ref-1/Ape1 binding to VEGF HRE sequences and blunted VEGF mRNA expression. Chromatin immunoprecipitation-sequence analysis of 8-oxoG distribution in hypoxic pulmonary artery endothelial cells showed that most of the oxidized base was localized to promoters with virtually no overlap between normoxic and hypoxic data sets. Transcription of genes whose promoters lost 8-oxoG during hypoxia was reduced, while those gaining 8-oxoG was elevated. Collectively, these findings suggest that the BER pathway links hypoxia-induced introduction of oxidative DNA modifications in promoters of hypoxia-inducible genes to transcriptional activation.


Assuntos
Dano ao DNA/genética , Reparo do DNA/genética , Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Sítios de Ligação , Hipóxia Celular/genética , Imunoprecipitação da Cromatina , Células Endoteliais/metabolismo , Guanina/análogos & derivados , Guanina/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Motivos de Nucleotídeos , Oxirredução , Artéria Pulmonar/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Elementos de Resposta/genética , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo
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