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1.
Nat Genet ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024998

RESUMO

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

2.
Nat Genet ; 52(1): 29-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31844324

RESUMO

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.

3.
Nat Commun ; 10(1): 3615, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399598

RESUMO

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.


Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenômica , Predisposição Genética para Doença/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos B/metabolismo , Sequência de Bases , Cromatina/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição
4.
Nat Genet ; 51(7): 1137-1148, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31253982

RESUMO

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.


Assuntos
Cromatina/química , Diabetes Mellitus Tipo 2/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Secreção de Insulina/genética , Ilhotas Pancreáticas/metabolismo , Cromatina/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Conformação Molecular , Regiões Promotoras Genéticas
5.
Blood ; 133(9): 940-951, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30538135

RESUMO

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.


Assuntos
Ciclina D2/genética , Ciclina D3/genética , Elementos Facilitadores Genéticos , Rearranjo Gênico , Cadeias Leves de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Idoso , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXC/genética , Translocação Genética
6.
Cancer Treat Res Commun ; 15: 21-31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30207284

RESUMO

OBJECTIVE: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. MATERIALS AND METHODS: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain). RESULTS: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients. CONCLUSION: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy. MICROABSTRACT: A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Progressão da Doença , Mutação em Linhagem Germinativa , Histona-Lisina N-Metiltransferase/genética , Neoplasias Pulmonares/tratamento farmacológico , Platina/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Neoplasias Pulmonares/genética , Masculino , Estadiamento de Neoplasias , Prognóstico , Espanha
7.
Proc Natl Acad Sci U S A ; 115(38): E8900-E8908, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30181294

RESUMO

Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4CT232) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4CT232 allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4CT232 exhibit increased levels of DNA damage and are sensitized to several conditions that increase chromosome missegregation, including DNA replication stress, inhibition of the mitotic checkpoint, and loss of p53. Our data demonstrate the biological importance of the abscission checkpoint and suggest that dysregulation of abscission by CHMP4CT232 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Predisposição Genética para Doença/genética , Instabilidade Genômica/genética , Neoplasias/genética , Proteínas de Ligação ao Cálcio/metabolismo , Carcinogênese/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cromatina/metabolismo , Cristalografia por Raios X , Dano ao DNA/genética , Replicação do DNA/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Mitose/genética , Fosforilação , Polimorfismo Genético , RNA Interferente Pequeno/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
8.
J Med Genet ; 55(11): 765-778, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30166351

RESUMO

BACKGROUND: Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation. METHODS: We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107). RESULTS: Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9×10-9) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4×10-10) and variants in IRF4 (p=2.8×10-57), SLC45A2 (p=2.2×10-130), HERC2 (p=2.8×10-176), OCA2 (p=2.4×10-121) and MC1R (p=7.7×10-22) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold <5×10-9) at ZRANB2-AS2, PIK3R1, EPHA7, MAD1L1, CACUL1 and MAP3K9. CONCLUSION: Considering multiple-related genetic phenotypes improve associated genome signal detection. These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits.


Assuntos
Variação Biológica Individual , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Característica Quantitativa Herdável , Antropometria , Feminino , Genótipo , Humanos , Padrões de Herança , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigilância em Saúde Pública , Medição de Risco
9.
Arthritis Res Ther ; 20(1): 100, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848360

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE. METHODS: We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software. RESULTS: We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10- 8): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10- 6), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10- 5), interleukin-4 signaling (p = 3.97 × 10- 5) and cell surface interactions at the vascular wall (p = 4.63 × 10- 5). CONCLUSIONS: Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Estudos de Coortes , Variação Genética/genética , Humanos
10.
Nat Commun ; 9(1): 2162, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29849136

RESUMO

In the originally published version of this Article, the affiliation details for Santi González, Jian'an Luan and Claudia Langenberg were inadvertently omitted. Santi González should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain', and Jian'an Luan and Claudia Langenberg should have been affiliated with 'MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK'. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article.

11.
Kidney Int ; 94(2): 363-371, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29801666

RESUMO

Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.


Assuntos
Testes Genéticos/métodos , Nefrite Hereditária/diagnóstico , Rim Policístico Autossômico Dominante/diagnóstico , Diagnóstico Pré-Natal/métodos , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Custo-Benefício , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/métodos , Estudos de Viabilidade , Feminino , Testes Genéticos/economia , Sequenciamento de Nucleotídeos em Larga Escala/economia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Rim/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Nefrite Hereditária/epidemiologia , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Fenótipo , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , Gravidez , Diagnóstico Pré-Natal/economia , Prevalência , Adulto Jovem
12.
Nat Med ; 24(6): 868-880, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29785028

RESUMO

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.


Assuntos
Cromatina/metabolismo , Epigenômica , Leucemia Linfocítica Crônica de Células B/genética , Linfócitos B/metabolismo , Sequência de Bases , Estudos de Coortes , Humanos
13.
Nat Commun ; 9(1): 321, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29358691

RESUMO

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.


Assuntos
Cromossomos Humanos X/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Alelos , Redes Reguladoras de Genes/genética , Genótipo , Humanos , Resistência à Insulina/genética , Masculino , Modelos Genéticos , Fatores de Risco
14.
Sci Rep ; 7(1): 10500, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874741

RESUMO

Lambda interferons (IFNLs) have immunomodulatory functions at epithelial barrier surfaces. IFN-λ4, a recent member of this family is expressed only in a subset of the population due to a frameshift-causing DNA polymorphism rs368234815. We examined the association of this polymorphism with atopy (aeroallergen sensitization) and asthma in a Polish hospital-based case-control cohort comprising of well-characterized adult asthmatics (n = 326) and healthy controls (n = 111). In the combined cohort, we saw no association of the polymorphism with asthma and/or atopy. However, the IFN-λ4-generating ΔG allele protected older asthmatic women (>50 yr of age) from atopic sensitization. Further, ΔG allele significantly associated with features of less-severe asthma including bronchodilator response and corticosteroid usage in older women in this Polish cohort. We tested the association of related IFNL locus polymorphisms (rs12979860 and rs8099917) with atopy, allergic rhinitis and presence/absence of asthma in three population-based cohorts from Europe, but saw no significant association of the polymorphisms with any of the phenotypes in older women. The polymorphisms associated marginally with lower occurrence of asthma in men/older men after meta-analysis of data from all cohorts. Functional and well-designed replication studies may reveal the true positive nature of these results.


Assuntos
Alérgenos/imunologia , Asma/etiologia , Asma/metabolismo , Interferon gama/metabolismo , Polimorfismo Genético , Adulto , Idoso , Alelos , Asma/diagnóstico , Estudos de Casos e Controles , Feminino , Frequência do Gene , Loci Gênicos , Genótipo , Humanos , Imunização , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polônia , Polimorfismo de Nucleotídeo Único
16.
Nat Med ; 23(7): 850-858, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530702

RESUMO

Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.


Assuntos
DNA Bacteriano/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Animais , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Método Duplo-Cego , Ácidos Graxos Voláteis/metabolismo , Transplante de Microbiota Fecal , Fezes/química , Fezes/microbiologia , Feminino , Vida Livre de Germes , Teste de Tolerância a Glucose , Humanos , Técnicas In Vitro , Masculino , Metagenômica , Camundongos , Pessoa de Meia-Idade
17.
Nat Genet ; 49(7): 1005-1014, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28504702

RESUMO

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.


Assuntos
Transformação Celular Neoplásica/genética , Tumor Rabdoide/genética , Transposases/fisiologia , Adulto , Animais , Domínio Catalítico , Linhagem Celular , Criança , Pré-Escolar , Aberrações Cromossômicas , Pontos de Quebra do Cromossomo , Reparo do DNA por Junção de Extremidades/genética , DNA de Neoplasias/genética , Rearranjo Gênico/genética , Genes Supressores de Tumor , Humanos , Lactente , Camundongos , Camundongos Nus , Mutagênese Sítio-Dirigida , Interferência de RNA , Proteínas Recombinantes/metabolismo , Sequências Reguladoras de Ácido Nucleico , Sequências Repetidas Terminais/genética , Transposases/química , Transposases/genética
18.
J Clin Endocrinol Metab ; 102(7): 2584-2594, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28368446

RESUMO

Context: Human placenta exhibits a specific microRNA (miRNA) expression pattern. Some of these miRNAs are dysregulated in pregnancy disorders such as preeclampsia and intrauterine growth restriction and are potential biomarkers for these pathologies. Objective: To study the placental miRNA profile in pregnant women with pregestational overweight/obesity (preOB) or gestational obesity (gestOB) and explore the associations between placental miRNAs dysregulated in maternal obesity and prenatal and postnatal growth. Methods: TaqMan Low Density Arrays and real-time polymerase chain reaction were used to profile the placental miRNAs in 70 pregnant women (20 preOB, 25 gestOB, and 25 control). Placentas and newborns were weighed at delivery, and infants were weighed at 1, 4, and 12 months of age. Results: Eight miRNAs were decreased in placentas from preOB or gestOB (miR-100, miR-1269, miR-1285, miR-181, miR-185, miR-214, miR-296, and miR-487) (all P < 0.05). Among them, miR-100, miR-1285, miR-296, and miR-487 were associated with maternal metabolic parameters (all P < 0.05) and were predictors of lower birth weight (all P < 0.05; R2 > 30%) and increased postnatal weight gain (all P < 0.05; R2 > 20%). In silico analysis showed that these miRNAs were related to cell proliferation and insulin signaling pathways. miR-296 was also present in plasma samples and associated with placental expression and prenatal and postnatal growth parameters (all P < 0.05). Conclusions: We identified a specific placental miRNA profile in maternal obesity. Placental miRNAs dysregulated in maternal obesity may be involved in mediation of growth-promoting effects of maternal obesity on offspring and could be used as early markers of prenatal and postnatal growth.


Assuntos
Desenvolvimento Fetal/fisiologia , MicroRNAs/metabolismo , Obesidade/diagnóstico , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Adulto , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Desenvolvimento Infantil/fisiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/diagnóstico , Diagnóstico Pré-Natal/métodos , Valores de Referência , Sensibilidade e Especificidade , Ganho de Peso/fisiologia
19.
Cell Syst ; 3(5): 491-495.e5, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27863955

RESUMO

The impact of large and complex epigenomic datasets on biological insights or clinical applications is limited by the lack of accessibility by easy, intuitive, and fast tools. Here, we describe an epigenomics comparative cyber-infrastructure (EPICO), an open-access reference set of libraries to develop comparative epigenomic data portals. Using EPICO, large epigenome projects can make available their rich datasets to the community without requiring specific technical skills. As a first instance of EPICO, we implemented the BLUEPRINT Data Analysis Portal (BDAP). BDAP provides a desktop for the comparative analysis of epigenomes of hematopoietic cell types based on results, such as the position of epigenetic features, from basic analysis pipelines. The BDAP interface facilitates interactive exploration of genomic regions, genes, and pathways in the context of differentiation of hematopoietic lineages. This work represents initial steps toward broadly accessible integrative analysis of epigenomic data across international consortia. EPICO can be accessed at https://github.com/inab, and BDAP can be accessed at http://blueprint-data.bsc.es.


Assuntos
Epigenômica , Diferenciação Celular , Epigênese Genética , Genoma , Internet , Software , Interface Usuário-Computador
20.
ISME J ; 10(8): 1902-14, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26784354

RESUMO

Most free-living planktonic cells are streamlined and in spite of their limitations in functional flexibility, their vast populations have radiated into a wide range of aquatic habitats. Here we compared the metabolic potential of subgroups in the Alphaproteobacteria lineage SAR11 adapted to marine and freshwater habitats. Our results suggest that the successful leap from marine to freshwaters in SAR11 was accompanied by a loss of several carbon degradation pathways and a rewiring of the central metabolism. Examples for these are C1 and methylated compounds degradation pathways, the Entner-Doudouroff pathway, the glyoxylate shunt and anapleuretic carbon fixation being absent from the freshwater genomes. Evolutionary reconstructions further suggest that the metabolic modules making up these important freshwater metabolic traits were already present in the gene pool of ancestral marine SAR11 populations. The loss of the glyoxylate shunt had already occurred in the common ancestor of the freshwater subgroup and its closest marine relatives, suggesting that the adaptation to freshwater was a gradual process. Furthermore, our results indicate rapid evolution of TRAP transporters in the freshwater clade involved in the uptake of low molecular weight carboxylic acids. We propose that such gradual tuning of metabolic pathways and transporters toward locally available organic substrates is linked to the formation of subgroups within the SAR11 clade and that this process was critical for the freshwater clade to find and fix an adaptive phenotype.


Assuntos
Alphaproteobacteria/metabolismo , Carbono/metabolismo , Plâncton/genética , Adaptação Fisiológica , Alphaproteobacteria/genética , Evolução Biológica , Ecossistema , Água Doce/microbiologia , Fenótipo , Filogenia , Plâncton/metabolismo
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