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1.
Nature ; 595(7866): 309-314, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33953401

RESUMO

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.


Assuntos
Inativação Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Animais , Antígenos Virais/imunologia , Sistemas CRISPR-Cas/genética , Cromatina/genética , Cromatina/metabolismo , Elementos de DNA Transponíveis/genética , Modelos Animais de Doenças , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia
2.
Nature ; 593(7858): 238-243, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33828297

RESUMO

Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.


Assuntos
Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença , Variação Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Linhagem Celular , Cromossomos Humanos Par 10/genética , Ciclofilinas/genética , Células Dendríticas , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Mitocôndrias/metabolismo , Especificidade de Órgãos/genética , Fenótipo
3.
J Invasive Cardiol ; 32(7): 276-282, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32610269

RESUMO

Contrast-associated acute kidney injury, resulting from the use of iodinated contrast media, is a well-known adverse event following endovascular procedures and is associated with poor prognosis when it happens. There is an abundance of literature studying acute kidney injury following percutaneous coronary interventions, with very few studies done in the setting of percutaneous peripheral intervention. Although both percutaneous coronary intervention and percutaneous peripheral intervention utilize iodinated contrast media, several differences exist that can affect the incidence and management of contrast-associated acute kidney injury. This article aims to review what we currently know about contrast-associated acute kidney injury and available prevention strategies, specifically following percutaneous peripheral interventions.


Assuntos
Injúria Renal Aguda , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Meios de Contraste/efeitos adversos , Humanos , Compostos de Iodo , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco
4.
medRxiv ; 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32587989

RESUMO

Public health agencies have recommended that the public wear face coverings, including face masks, to mitigate COVID-19 transmission. However, the extent to which the public has adopted this recommendation is unknown. An observational study of 3,271 members of the public in May and June 2020 examined face covering use at grocery stores across Wisconsin. We found that only 41.2% used face coverings. Individuals who appeared to be female or older adults had higher odds of using face coverings. Additionally, location-specific variables such as expensiveness of store, county-level population and county-level COVID-19 case prevalence were associated with increased odds of using face coverings. To our knowledge, this is the first direct observational study examining face covering behavior by the public in the U.S., and our findings have implications for public health agencies during the COVID-19 pandemic.

5.
Nat Genet ; 51(12): 1664-1669, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31784727

RESUMO

Enhancer elements in the human genome control how genes are expressed in specific cell types and harbor thousands of genetic variants that influence risk for common diseases1-4. Yet, we still do not know how enhancers regulate specific genes, and we lack general rules to predict enhancer-gene connections across cell types5,6. We developed an experimental approach, CRISPRi-FlowFISH, to perturb enhancers in the genome, and we applied it to test >3,500 potential enhancer-gene connections for 30 genes. We found that a simple activity-by-contact model substantially outperformed previous methods at predicting the complex connections in our CRISPR dataset. This activity-by-contact model allows us to construct genome-wide maps of enhancer-gene connections in a given cell type, on the basis of chromatin state measurements. Together, CRISPRi-FlowFISH and the activity-by-contact model provide a systematic approach to map and predict which enhancers regulate which genes, and will help to interpret the functions of the thousands of disease risk variants in the noncoding genome.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Elementos Facilitadores Genéticos , Regiões Promotoras Genéticas , Animais , Fator de Transcrição GATA1/genética , Regulação da Expressão Gênica , Desacetilase 6 de Histona/genética , Humanos , Hibridização in Situ Fluorescente , Células K562 , Camundongos , Modelos Genéticos , RNA Guia
6.
Proc Natl Acad Sci U S A ; 115(30): E7222-E7230, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29987030

RESUMO

Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. TF binding occurs in nucleosome-depleted regions of DNA (NDRs), which generally encompass regions with lengths similar to those protected by nucleosomes. However, less is known about where within these regions specific TFs tend to be found. Here, we characterize the positional bias of inferred binding sites for 103 TFs within ∼500,000 NDRs across 47 cell types. We find that distinct classes of TFs display different binding preferences: Some tend to have binding sites toward the edges, some toward the center, and some at other positions within the NDR. These patterns are highly consistent across cell types, suggesting that they may reflect TF-specific intrinsic structural or functional characteristics. In particular, TF classes with binding sites at NDR edges are enriched for those known to interact with histones and chromatin remodelers, whereas TFs with central enrichment interact with other TFs and cofactors such as p300. Our results suggest distinct regiospecific binding patterns and functions of TF classes within enhancers.


Assuntos
Regulação da Expressão Gênica/fisiologia , Elementos de Resposta/fisiologia , Fatores de Transcrição/metabolismo , Humanos , Células Jurkat , Fatores de Transcrição/genética , Células U937
7.
J Clin Invest ; 125(8): 3178-92, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26121745

RESUMO

Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3-like-1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3-dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.


Assuntos
Adipocinas/sangue , Apoptose , Glicoproteínas/sangue , Síndrome de Hermanski-Pudlak/sangue , Lectinas/sangue , Fibrose Pulmonar/sangue , Mucosa Respiratória/metabolismo , Adipocinas/genética , Adulto , Animais , Biomarcadores/sangue , Proteína 1 Semelhante à Quitinase-3 , Modelos Animais de Doenças , Feminino , Glicoproteínas/genética , Síndrome de Hermanski-Pudlak/complicações , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/patologia , Humanos , Subunidade alfa2 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Lectinas/genética , Masculino , Camundongos , Camundongos Knockout , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Mucosa Respiratória/patologia
8.
Cardiovasc Ultrasound ; 9: 18, 2011 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-21645399

RESUMO

A 51-year-old female undergoing an outpatient stress echocardiogram to evaluate atypical chest pain developed acute ST elevation in the anterior precordial leads on electrocardiogram following exercise. Echocardiography revealed a severe rise in pulmonary artery systolic pressure (PASP) with marked right ventricular (RV) enlargement and interventricular septum flattening. Subsequently, cardiac catherization confirmed an exercise-induced elevation in PASP and diagnosed pulmonary arterial hypertension without evidence of coronary artery disease. This case suggests that an acute elevation in pulmonary artery pressure with RV dilation may be a potential cause of acute ST elevation during stress testing.


Assuntos
Dor no Peito/diagnóstico , Doença das Coronárias/diagnóstico , Ecocardiografia sob Estresse/métodos , Eletrocardiografia , Hipertensão Pulmonar/diagnóstico por imagem , Cateterismo Cardíaco/métodos , Dor no Peito/etiologia , Doença das Coronárias/diagnóstico por imagem , Diagnóstico Diferencial , Ecocardiografia sob Estresse/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Pessoa de Meia-Idade , Medição de Risco
9.
J Vet Med Sci ; 73(2): 209-15, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20948168

RESUMO

The epidemiological information has obtained on avian influenza virus (AIV) in eastern Hokkaido, Japan, where AIV surveillance has not been performed. Cloacal or fecal samples obtained from migratory water birds were screened for AIV both by real-time reverse transcriptase polymerase chain reaction to detect the influenza A virus matrix (M) gene and by egg inoculation. Between 2007 and 2009, a total of 2,488 samples were collected from various avian species in Abashiri, Kushiro, Nemuro and Tokachi districts of eastern Hokkaido. AIVs were isolated from 18 of those samples (0.7%). No AIV was isolated from the 1,449 samples collected in Abashiri, Kushiro and Nemuro districts, although 6 were positive for the M gene by RRT-PCR. In contrast, 52 (5.0%) of the 1,039 samples collected from ducks in Tokachi district were M gene positive; AIVs were isolated from 18 of those samples (1.7%). The isolates included H3N5 (1 isolate), H3N6 (1), H3N8 (9), H4N2 (1), H4N6 (2), H6N5 (1), H6N8 (1), and H11N3 (2) subtypes. H3N5 and H11N3 subtypes have not been frequently isolated, and our study is the first to report H3N5 and the second to report H11N3 in Japan. Phylogenetic analysis revealed that the M genes of all isolates belonged to the Eurasian lineage.


Assuntos
Vírus da Influenza A/isolamento & purificação , Influenza Aviária/virologia , Animais , Animais Selvagens , Aves , Vírus da Influenza A/genética , Influenza Aviária/epidemiologia , Japão/epidemiologia , Filogenia , RNA Viral/química , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Análise de Sequência de DNA , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética
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