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1.
Cell ; 150(5): 1068-81, 2012 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-22939629

RESUMEN

Cellular processes often depend on stable physical associations between proteins. Despite recent progress, knowledge of the composition of human protein complexes remains limited. To close this gap, we applied an integrative global proteomic profiling approach, based on chromatographic separation of cultured human cell extracts into more than one thousand biochemical fractions that were subsequently analyzed by quantitative tandem mass spectrometry, to systematically identify a network of 13,993 high-confidence physical interactions among 3,006 stably associated soluble human proteins. Most of the 622 putative protein complexes we report are linked to core biological processes and encompass both candidate disease genes and unannotated proteins to inform on mechanism. Strikingly, whereas larger multiprotein assemblies tend to be more extensively annotated and evolutionarily conserved, human protein complexes with five or fewer subunits are far more likely to be functionally unannotated or restricted to vertebrates, suggesting more recent functional innovations.


Asunto(s)
Complejos Multiproteicos/análisis , Mapas de Interacción de Proteínas , Proteínas/química , Proteómica/métodos , Humanos , Espectrometría de Masas en Tándem
2.
Mol Cell ; 55(5): 791-802, 2014 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-25155612

RESUMEN

Mechanistic roles for many lncRNAs are poorly understood, in part because their direct interactions with genomic loci and proteins are difficult to assess. Using a method to purify endogenous RNAs and their associated factors, we mapped the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs. We also identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation alters localization of NEAT1 on active chromatin sites, implying that underlying DNA sequence does not target NEAT1 to chromatin, and that localization responds to cues involved in the transcription process.


Asunto(s)
Cromatina/metabolismo , ARN Largo no Codificante/metabolismo , Sitios de Unión , Humanos , Modelos Genéticos , Hibridación de Ácido Nucleico , ARN Largo no Codificante/análisis , ARN Largo no Codificante/química , Transcripción Genética
3.
Genome Res ; 21(7): 1109-21, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21536720

RESUMEN

Network "guilt by association" (GBA) is a proven approach for identifying novel disease genes based on the observation that similar mutational phenotypes arise from functionally related genes. In principle, this approach could account even for nonadditive genetic interactions, which underlie the synergistic combinations of mutations often linked to complex diseases. Here, we analyze a large-scale, human gene functional interaction network (dubbed HumanNet). We show that candidate disease genes can be effectively identified by GBA in cross-validated tests using label propagation algorithms related to Google's PageRank. However, GBA has been shown to work poorly in genome-wide association studies (GWAS), where many genes are somewhat implicated, but few are known with very high certainty. Here, we resolve this by explicitly modeling the uncertainty of the associations and incorporating the uncertainty for the seed set into the GBA framework. We observe a significant boost in the power to detect validated candidate genes for Crohn's disease and type 2 diabetes by comparing our predictions to results from follow-up meta-analyses, with incorporation of the network serving to highlight the JAK-STAT pathway and associated adaptors GRB2/SHC1 in Crohn's disease and BACH2 in type 2 diabetes. Consideration of the network during GWAS thus conveys some of the benefits of enrolling more participants in the GWAS study. More generally, we demonstrate that a functional network of human genes provides a valuable statistical framework for prioritizing candidate disease genes, both for candidate gene-based and GWAS-based studies.


Asunto(s)
Enfermedad de Crohn/genética , Diabetes Mellitus Tipo 2/genética , Genoma Humano , Estudio de Asociación del Genoma Completo/métodos , Algoritmos , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Estudios de Seguimiento , Proteína Adaptadora GRB2/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Metaanálisis como Asunto , Ratones , Modelos Biológicos , Modelos Estadísticos , Fenotipo , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras de la Señalización Shc/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src
4.
Am J Prev Med ; 54(2): 197-204, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29249555

RESUMEN

INTRODUCTION: A number of locations have been considering sugar-sweetened beverage point-of-purchase warning label policies to help address rising adolescent overweight and obesity prevalence. METHODS: To explore the impact of such policies, in 2016 detailed agent-based models of Baltimore, Philadelphia, and San Francisco were developed, representing their populations, school locations, and food sources, using data from various sources collected between 2005 and 2014. The model simulated, over a 7-year period, the mean change in BMI and obesity prevalence in each of the cities from sugar-sweetened beverage warning label policies. RESULTS: Data analysis conducted between 2016 and 2017 found that implementing sugar-sweetened beverage warning labels at all sugar-sweetened beverage retailers lowered obesity prevalence among adolescents in all three cities. Point-of-purchase labels with 8% efficacy (i.e., labels reducing probability of sugar-sweetened beverage consumption by 8%) resulted in the following percentage changes in obesity prevalence: Baltimore: -1.69% (95% CI= -2.75%, -0.97%, p<0.001); San Francisco: -4.08% (95% CI= -5.96%, -2.2%, p<0.001); Philadelphia: -2.17% (95% CI= -3.07%, -1.42%, p<0.001). CONCLUSIONS: Agent-based simulations showed how warning labels may decrease overweight and obesity prevalence in a variety of circumstances with label efficacy and literacy rate identified as potential drivers. Implementing a warning label policy may lead to a reduction in obesity prevalence. Focusing on warning label design and store compliance, especially at supermarkets, may further increase the health impact.


Asunto(s)
Bebidas/efectos adversos , Modelos Biológicos , Edulcorantes Nutritivos/efectos adversos , Sobrepeso/prevención & control , Etiquetado de Productos/métodos , Adolescente , Baltimore/epidemiología , Niño , Ingestión de Energía , Femenino , Humanos , Masculino , Sobrepeso/epidemiología , Sobrepeso/etiología , Philadelphia/epidemiología , Prevalencia , San Francisco/epidemiología , Instituciones Académicas , Análisis de Sistemas
5.
PLoS One ; 12(8): e0182568, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28796844

RESUMEN

In mammals, monoallelic gene expression can result from X-chromosome inactivation, genomic imprinting, and random monoallelic expression (RMAE). Epigenetic regulation of RMAE is not fully understood. Here we analyze allelic imbalance in chromatin state of autosomal genes using ChIP-seq in a clonal cell line. We identify approximately 3.7% of autosomal genes that show significant differences between chromatin states of two alleles. Allelic regulation is represented among several functional gene categories including histones, chromatin modifiers, and multiple early developmental regulators. Most cases of allelic skew are produced by quantitative differences between two allelic chromatic states that belong to the same gross type (active, silent, or bivalent). Combinations of allelic states of different types are possible but less frequent. When different chromatin marks are skewed on the same gene, their skew is coordinated as a result of quantitative relationships between these marks on each individual allele. Finally, combination of allele-specific densities of chromatin marks is a quantitative predictor of allelic skew in gene expression.


Asunto(s)
Desequilibrio Alélico , Cromatina/genética , Alelos , Animales , Línea Celular , Epigénesis Genética , Femenino , Fibroblastos/metabolismo , Expresión Génica , Genoma , Impresión Genómica , Masculino , Ratones , Ratones de la Cepa 129
6.
Dev Cell ; 43(3): 359-371.e6, 2017 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-29107559

RESUMEN

X-chromosome inactivation (XCI) silences one X chromosome in the female mammal and is essential to peri-implantation development. XCI is thought to be cell autonomous, with all factors required being produced within each cell. Nevertheless, external cues may exist. Here, we search for such developmental signals by combining bioinformatic, biochemical, and genetic approaches. Using ex vivo and in vivo models, we identify the Hedgehog (HH) paracrine system as a candidate signaling cascade. HH signaling keeps XCI in check in pluripotent cells and is transduced by GLI transcription factors to binding sites in Tsix, the antisense repressor of XCI. GLI potentiates Tsix expression and impedes XCI. In vivo, mutating Indian Hedgehog results in a sex ratio bias against females, and the female lethality is rescued by a second-site mutation in Tsix. These data demonstrate a genetic and functional intersection between HH and XCI and support a role for intercellular signaling during XCI.


Asunto(s)
Proteínas Hedgehog/metabolismo , Regiones Promotoras Genéticas/genética , ARN Largo no Codificante/genética , Inactivación del Cromosoma X/genética , Animales , Diferenciación Celular/fisiología , Femenino , Ratones Noqueados , Factores de Transcripción/metabolismo , Transcripción Genética/genética
7.
Health Aff (Millwood) ; 36(5): 902-908, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28461358

RESUMEN

Increasing physical activity among children is a potentially important public health intervention. Quantifying the economic and health effects of the intervention would help decision makers understand its impact and priority. Using a computational simulation model that we developed to represent all US children ages 8-11 years, we estimated that maintaining the current physical activity levels (only 31.9 percent of children get twenty-five minutes of high-calorie-burning physical activity three times a week) would result each year in a net present value of $1.1 trillion in direct medical costs and $1.7 trillion in lost productivity over the course of their lifetimes. If 50 percent of children would exercise, the number of obese and overweight youth would decrease by 4.18 percent, averting $8.1 billion in direct medical costs and $13.8 billion in lost productivity. Increasing the proportion of children who exercised to 75 percent would avert $16.6 billion and $23.6 billion, respectively.


Asunto(s)
Costo de Enfermedad , Ejercicio Físico/fisiología , Costos de la Atención en Salud/tendencias , Niño , Eficiencia , Humanos , Modelos Estadísticos , Obesidad Infantil/economía , Obesidad Infantil/prevención & control
8.
Science ; 355(6329): 1081-1084, 2017 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-28280206

RESUMEN

Nucleosomes play important structural and regulatory roles by tightly wrapping the DNA that constitutes the metazoan genome. The Polycomb group (PcG) proteins modulate nucleosomes to maintain repression of key developmental genes, including Hox genes whose temporal and spatial expression is tightly regulated to guide patterning of the anterior-posterior body axis. CBX2, a component of the mammalian Polycomb repressive complex 1 (PRC1), contains a compaction region that has the biochemically defined activity of bridging adjacent nucleosomes. Here, we demonstrate that a functional compaction region is necessary for proper body patterning, because mutating this region leads to homeotic transformations similar to those observed with PcG loss-of-function mutations. We propose that CBX2-driven nucleosome compaction is a key mechanism by which PcG proteins maintain gene silencing during mouse development.


Asunto(s)
Tipificación del Cuerpo/genética , Regulación del Desarrollo de la Expresión Génica , Silenciador del Gen , Genes Homeobox , Nucleosomas/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Animales , Línea Celular , Ratones , Ratones Mutantes , Mutación , Nucleosomas/genética , Complejo Represivo Polycomb 1/genética , Unión Proteica , Esqueleto/crecimiento & desarrollo
9.
Elife ; 3: e02833, 2014 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-25082344

RESUMEN

The bithorax complex (BX-C) in Drosophila melanogaster is a cluster of homeotic genes that determine body segment identity. Expression of these genes is governed by cis-regulatory domains, one for each parasegment. Stable repression of these domains depends on Polycomb Group (PcG) functions, which include trimethylation of lysine 27 of histone H3 (H3K27me3). To search for parasegment-specific signatures that reflect PcG function, chromatin from single parasegments was isolated and profiled. The H3K27me3 profiles across the BX-C in successive parasegments showed a 'stairstep' pattern that revealed sharp boundaries of the BX-C regulatory domains. Acetylated H3K27 was broadly enriched across active domains, in a pattern complementary to H3K27me3. The CCCTC-binding protein (CTCF) bound the borders between H3K27 modification domains; it was retained even in parasegments where adjacent domains lack H3K27me3. These findings provide a molecular definition of the homeotic domains, and implicate precisely positioned H3K27 modifications as a central determinant of segment identity.


Asunto(s)
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epigénesis Genética , Genes Homeobox , Histonas/genética , Complejo Represivo Polycomb 1/genética , Proteínas Represoras/genética , Acetilación , Animales , Tipificación del Cuerpo/genética , Factor de Unión a CCCTC , Cromatina/química , Cromatina/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Embrión no Mamífero , Femenino , Regulación del Desarrollo de la Expresión Génica , Histonas/metabolismo , Lisina/metabolismo , Masculino , Complejo Represivo Polycomb 1/metabolismo , Unión Proteica , Proteínas Represoras/metabolismo , Transducción de Señal
10.
Genome Biol ; 13(12): R125, 2012 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-23268829

RESUMEN

The growing availability of large-scale functional networks has promoted the development of many successful techniques for predicting functions of genes. Here we extend these network-based principles and techniques to functionally characterize whole sets of genes. We present RIDDLE (Reflective Diffusion and Local Extension), which uses well developed guilt-by-association principles upon a human gene network to identify associations of gene sets. RIDDLE is particularly adept at characterizing sets with no annotations, a major challenge where most traditional set analyses fail. Notably, RIDDLE found microRNA-450a to be strongly implicated in ocular diseases and development. A web application is available at http://www.functionalnet.org/RIDDLE.


Asunto(s)
Redes Reguladoras de Genes , Programas Informáticos , Animales , Oftalmopatías/genética , Genómica/métodos , Humanos , Ratones , MicroARNs/metabolismo , Anotación de Secuencia Molecular
11.
Cytoskeleton (Hoboken) ; 68(2): 112-24, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21246755

RESUMEN

Cytokinesis and ciliogenesis are fundamental cellular processes that require strict coordination of microtubule organization and directed membrane trafficking. These processes have been intensely studied, but there has been little indication that regulatory machinery might be extensively shared between them. Here, we show that several central spindle/midbody proteins (PRC1, MKLP-1, INCENP, centriolin) also localize in specific patterns at the basal body complex in vertebrate ciliated epithelial cells. Moreover, bioinformatic comparisons of midbody and cilia proteomes reveal a highly significant degree of overlap. Finally, we used temperature-sensitive alleles of PRC1/spd-1 and MKLP-1/zen-4 in C. elegans to assess ciliary functions while bypassing these proteins' early role in cell division. These mutants displayed defects in both cilia function and cilia morphology. Together, these data suggest the conserved reuse of a surprisingly large number of proteins in the cytokinetic apparatus and in cilia.


Asunto(s)
Cilios/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Xenopus/metabolismo , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cilios/genética , Larva , Proteínas Asociadas a Microtúbulos/genética , Mutación , Proteínas de Xenopus/genética , Xenopus laevis
12.
J Proteomics ; 73(11): 2277-89, 2010 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-20637909

RESUMEN

Increasing knowledge about the organization of proteins into complexes, systems, and pathways has led to a flowering of theoretical approaches for exploiting this knowledge in order to better learn the functions of proteins and their roles underlying phenotypic traits and diseases. Much of this body of theory has been developed and tested in model organisms, relying on their relative simplicity and genetic and biochemical tractability to accelerate the research. In this review, we discuss several of the major approaches for computationally integrating proteomics and genomics observations into integrated protein networks, then applying guilt-by-association in these networks in order to identify genes underlying traits. Recent trends in this field include a rising appreciation of the modular network organization of proteins underlying traits or mutational phenotypes, and how to exploit such protein modularity using computational approaches related to the internet search algorithm PageRank. Many protein network-based predictions have recently been experimentally confirmed in yeast, worms, plants, and mice, and several successful approaches in model organisms have been directly translated to analyze human disease, with notable recent applications to glioma and breast cancer prognosis.


Asunto(s)
Enfermedad/genética , Fenotipo , Proteínas/análisis , Proteómica/métodos , Animales , Enfermedad/clasificación , Humanos , Neoplasias/genética , Neoplasias/patología , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Proteómica/tendencias
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