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2.
Cell Rep ; 24(10): 2784-2794, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30184510

RESUMO

Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils.


Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Cromatina/genética , Cromatina/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos
3.
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
4.
Genome Biol ; 18(1): 50, 2017 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-28283040

RESUMO

BACKGROUND: The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. RESULTS: We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. CONCLUSIONS: Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.


Assuntos
Alelos , Metilação de DNA , Epigênese Genética , Epigenômica , Variação Genética , Genoma Humano , Efeitos da Posição Cromossômica , Ilhas de CpG , Elementos Facilitadores Genéticos , Epigenômica/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Especificidade de Órgãos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
5.
Nat Commun ; 7: 13555, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27898055

RESUMO

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.


Assuntos
Metilação de DNA/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Ilhas de CpG/genética , Sangue Fetal/metabolismo , Humanos , Anotação de Sequência Molecular , Fatores de Tempo , Gêmeos Monozigóticos/genética
6.
Cell Rep ; 17(8): 2101-2111, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27851971

RESUMO

DNA methylation and the localization and post-translational modification of nucleosomes are interdependent factors that contribute to the generation of distinct phenotypes from genetically identical cells. With 112 whole-genome bisulfite sequencing datasets from the BLUEPRINT Epigenome Project, we analyzed the global development of DNA methylation patterns during lineage commitment and maturation of a range of immune system effector cells and the cancers that arise from them. We show clear trends in methylation patterns that are distinct in the innate and adaptive arms of the human immune system, both globally and in relation to consistently positioned nucleosomes. Most notable are a progressive loss of methylation in developing lymphocytes and the consistent occurrence of non-CG methylation in specific cell types. Cancer samples from the two lineages are further polarized, suggesting the involvement of distinct lineage-specific epigenetic mechanisms. We anticipate broad utility for this resource as a basis for further comparative epigenetic analyses.


Assuntos
Imunidade Adaptativa/genética , Metilação de DNA/genética , Imunidade Inata/genética , Linfócitos B/metabolismo , Sequência de Bases , Sítios de Ligação , Fator de Ligação a CCCTC , Fosfatos de Dinucleosídeos/genética , Éxons/genética , Humanos , Linfócitos/metabolismo , Células Mieloides/metabolismo , Nucleossomos
7.
Cell ; 167(5): 1398-1414.e24, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27863251

RESUMO

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.


Assuntos
Epigenômica , Doenças do Sistema Imunitário/genética , Monócitos/metabolismo , Neutrófilos/metabolismo , Linfócitos T/metabolismo , Transcrição Genética , Adulto , Idoso , Processamento Alternativo , Feminino , Predisposição Genética para Doença , Células-Tronco Hematopoéticas/metabolismo , Código das Histonas , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Adulto Jovem
8.
Cancer Cell ; 30(5): 806-821, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27846393

RESUMO

We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.


Assuntos
Metilação de DNA , Elementos Facilitadores Genéticos , Epigenômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma de Célula do Manto/genética , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Simulação por Computador , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição SOXC/genética
9.
Nat Genet ; 47(7): 746-56, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26053498

RESUMO

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.


Assuntos
Linfócitos B/fisiologia , Metilação de DNA , Epigênese Genética/imunologia , Sequência de Bases , Diferenciação Celular , Células Cultivadas , Ilhas de CpG , Regulação Leucêmica da Expressão Gênica , Genoma Humano , Humanos , Leucemia de Células B/genética , Análise de Sequência de DNA
10.
Genome Res ; 25(4): 478-87, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25644835

RESUMO

While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.


Assuntos
Metilação de DNA/genética , Elementos Facilitadores Genéticos/genética , Mieloma Múltiplo/genética , Células-Tronco Neoplásicas/citologia , Plasmócitos/citologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Ilhas de CpG/genética , DNA de Neoplasias/genética , Regulação para Baixo/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Humanos , Regiões Promotoras Genéticas , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
11.
J Bioinform Comput Biol ; 12(5): 1450026, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25245144

RESUMO

Recent evidences suggest that a substantial amount of genome is transcribed more than that was anticipated, giving rise to a large number of unknown or novel transcripts. Identification of novel transcripts can provide key insights into understanding important cellular functions as well as molecular mechanisms underlying complex diseases like cancer. RNA-Seq has emerged as a powerful tool to detect novel transcripts, which previous profiling techniques failed to identify. A number of tools are available for enabling identification of novel transcripts at different levels. Read mappers such as TopHat, MapSplice, and SOAPsplice predict novel junctions, which are the indicators of novel transcripts. Cufflinks assembles novel transcripts based on alignment information and Oases performs de novo construction of transcripts. A common limitation of all these tools is prediction of sizable number of spurious or false positive (FP) novel transcripts. An approach that integrates information from all above sources and simultaneously scrutinizes FPs to correctly identify authentic novel transcripts of high confidence is proposed.


Assuntos
Análise de Sequência de RNA/métodos , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica/métodos , Humanos , Células MCF-7 , RNA/genética , Software
12.
Nat Methods ; 10(3): 221-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23353650

RESUMO

Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.


Assuntos
Biologia Computacional/métodos , Biologia Molecular/métodos , Anotação de Sequência Molecular , Proteínas/fisiologia , Algoritmos , Animais , Bases de Dados de Proteínas , Exorribonucleases/classificação , Exorribonucleases/genética , Exorribonucleases/fisiologia , Previsões , Humanos , Proteínas/química , Proteínas/classificação , Proteínas/genética , Especificidade da Espécie
13.
J Bioinform Comput Biol ; 10(4): 1250006, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22809419

RESUMO

Anvaya is a workflow environment for automated genome analysis that provides an interface for several bioinformatics tools and databases, loosely coupled together in a coordinated system, enabling the execution of a set of analyses tools in series or in parallel. It is a client-server workflow environment that has an advantage over existing software as it enables extensive pre & post processing of biological data in an efficient manner. "Anvaya" offers the user, novel functionalities to carry out exhaustive comparative analysis via "custom tools," which are tools with new functionality not available in standard tools, and "built-in PERL parsers," which automate data-flow between tools that hitherto, required manual intervention. It also provides a set of 11 pre-defined workflows for frequently used pipelines in genome annotation and comparative genomics ranging from EST assembly and annotation to phylogenetic reconstruction and microarray analysis. It provides a platform that serves as a single-stop solution for biologists to carry out hassle-free and comprehensive analysis, without being bothered about the nuances involved in tool installation, command line parameters, format conversions required to connect tools and manage/process multiple data sets at a single instance.


Assuntos
Genoma , Genômica/métodos , Software , Bases de Dados Factuais , Etiquetas de Sequências Expressas , Internet , Filogenia , Fluxo de Trabalho
14.
J Bacteriol ; 193(12): 3162-3, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21478351

RESUMO

Salmonella enterica is an animal and zoonotic pathogen of worldwide importance and may be classified into serovars differing in virulence and host range. We sequenced and annotated the genomes of serovar Typhimurium, Choleraesuis, Dublin, and Gallinarum strains of defined virulence in each of three food-producing animal hosts. This provides valuable measures of intraserovar diversity and opportunities to formally link genotypes to phenotypes in target animals.


Assuntos
Animais Domésticos , Alimentos , Genoma Bacteriano , Salmonelose Animal/microbiologia , Salmonella enterica/classificação , Salmonella enterica/genética , Animais , Dados de Sequência Molecular , Salmonella enterica/patogenicidade , Virulência
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