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1.
Cell ; 186(13): 2765-2782.e28, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37327786

RESUMEN

Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are enriched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs.


Asunto(s)
Metilación de ADN , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Carcinogénesis/genética , ADN , Epigénesis Genética , Neoplasias de la Próstata/genética , Células Neoplásicas Circulantes
2.
Cell ; 185(20): 3689-3704.e21, 2022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-36179666

RESUMEN

Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.


Asunto(s)
Cromatina , Placenta , Animales , Factor de Unión a CCCTC/metabolismo , Ensamble y Desensamble de Cromatina , Elementos de Facilitación Genéticos , Evolución Molecular , Femenino , Genoma , Mamíferos/metabolismo , Placenta/metabolismo , Embarazo , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Cell ; 181(5): 1062-1079.e30, 2020 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-32386547

RESUMEN

Expansions of amino acid repeats occur in >20 inherited human disorders, and many occur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Such diseases are associated with protein aggregation, but the contribution of aggregates to pathology has been controversial. Here, we report that alanine repeat expansions in the HOXD13 TF, which cause hereditary synpolydactyly in humans, alter its phase separation capacity and its capacity to co-condense with transcriptional co-activators. HOXD13 repeat expansions perturb the composition of HOXD13-containing condensates in vitro and in vivo and alter the transcriptional program in a cell-specific manner in a mouse model of synpolydactyly. Disease-associated repeat expansions in other TFs (HOXA13, RUNX2, and TBP) were similarly found to alter their phase separation. These results suggest that unblending of transcriptional condensates may underlie human pathologies. We present a molecular classification of TF IDRs, which provides a framework to dissect TF function in diseases associated with transcriptional dysregulation.


Asunto(s)
Expansión de las Repeticiones de ADN/genética , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Alanina/genética , Animales , Secuencia de Bases/genética , Expansión de las Repeticiones de ADN/fisiología , Modelos Animales de Enfermedad , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Mutación/genética , Linaje , Sindactilia/genética , Factores de Transcripción/metabolismo
4.
Cell ; 173(3): 624-633.e8, 2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29656892

RESUMEN

CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.


Asunto(s)
Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Epigénesis Genética , Mutación de Línea Germinal , Neoplasias/genética , Neoplasias/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Autofagia , Línea Celular Tumoral , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunoterapia , Ipilimumab/farmacología , Masculino , Melanoma/genética , Melanoma/inmunología , Antígenos Específicos del Melanoma/genética , Antígenos Específicos del Melanoma/inmunología , Ratones , Ratones Transgénicos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología
5.
Cell ; 167(5): 1310-1322.e17, 2016 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-27863245

RESUMEN

Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted.


Asunto(s)
Epigenómica , Células Madre Hematopoyéticas/citología , Animales , Linaje de la Célula , Células Clonales/citología , Fluorescencia , Hematopoyesis , Inflamación/patología , Ratones , Transcripción Genética
6.
Cell ; 162(2): 412-424, 2015 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-26186193

RESUMEN

Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here, we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered re-activation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies. PAPERCLIP.


Asunto(s)
Reprogramación Celular , Células Madre Pluripotentes Inducidas/citología , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Epigénesis Genética , Perfilación de la Expresión Génica , Histona Demetilasas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo
7.
Cell ; 159(7): 1681-97, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25525883

RESUMEN

Reprogramming to iPSCs resets the epigenome of somatic cells, including the reversal of X chromosome inactivation. We sought to gain insight into the steps underlying the reprogramming process by examining the means by which reprogramming leads to X chromosome reactivation (XCR). Analyzing single cells in situ, we found that hallmarks of the inactive X (Xi) change sequentially, providing a direct readout of reprogramming progression. Several epigenetic changes on the Xi occur in the inverse order of developmental X inactivation, whereas others are uncoupled from this sequence. Among the latter, DNA methylation has an extraordinary long persistence on the Xi during reprogramming, and, like Xist expression, is erased only after pluripotency genes are activated. Mechanistically, XCR requires both DNA demethylation and Xist silencing, ensuring that only cells undergoing faithful reprogramming initiate XCR. Our study defines the epigenetic state of multiple sequential reprogramming intermediates and establishes a paradigm for studying cell fate transitions during reprogramming.


Asunto(s)
Reprogramación Celular , Epigénesis Genética , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Cromosoma X/metabolismo , Animales , Proteínas Cdh1/metabolismo , Metilación de ADN , Proteínas de Homeodominio/metabolismo , Ratones , Proteína Homeótica Nanog , ARN Largo no Codificante/metabolismo
8.
Genes Dev ; 35(17-18): 1209-1228, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34413137

RESUMEN

The generation of myotubes from fibroblasts upon forced MyoD expression is a classic example of transcription factor-induced reprogramming. We recently discovered that additional modulation of signaling pathways with small molecules facilitates reprogramming to more primitive induced myogenic progenitor cells (iMPCs). Here, we dissected the transcriptional and epigenetic dynamics of mouse fibroblasts undergoing reprogramming to either myotubes or iMPCs using a MyoD-inducible transgenic model. Induction of MyoD in fibroblasts combined with small molecules generated Pax7+ iMPCs with high similarity to primary muscle stem cells. Analysis of intermediate stages of iMPC induction revealed that extinction of the fibroblast program preceded induction of the stem cell program. Moreover, key stem cell genes gained chromatin accessibility prior to their transcriptional activation, and these regions exhibited a marked loss of DNA methylation dependent on the Tet enzymes. In contrast, myotube generation was associated with few methylation changes, incomplete and unstable reprogramming, and an insensitivity to Tet depletion. Finally, we showed that MyoD's ability to bind to unique bHLH targets was crucial for generating iMPCs but dispensable for generating myotubes. Collectively, our analyses elucidate the role of MyoD in myogenic reprogramming and derive general principles by which transcription factors and signaling pathways cooperate to rewire cell identity.


Asunto(s)
Desarrollo de Músculos , Proteína MioD , Animales , Diferenciación Celular/genética , Ratones , Desarrollo de Músculos/genética , Fibras Musculares Esqueléticas , Músculo Esquelético , Proteína MioD/genética , Proteína MioD/metabolismo , Mioblastos/metabolismo , Células Madre/metabolismo
9.
Nat Rev Mol Cell Biol ; 17(3): 139-54, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26883001

RESUMEN

Differentiating somatic cells are progressively restricted to specialized functions during ontogeny, but they can be experimentally directed to form other cell types, including those with complete embryonic potential. Early nuclear reprogramming methods, such as somatic cell nuclear transfer (SCNT) and cell fusion, posed significant technical hurdles to precise dissection of the regulatory programmes governing cell identity. However, the discovery of reprogramming by ectopic expression of a defined set of transcription factors, known as direct reprogramming, provided a tractable platform to uncover molecular characteristics of cellular specification and differentiation, cell type stability and pluripotency. We discuss the control and maintenance of cellular identity during developmental transitions as they have been studied using direct reprogramming, with an emphasis on transcriptional and epigenetic regulation.


Asunto(s)
Diferenciación Celular , Reprogramación Celular , Expresión Génica Ectópica , Epigénesis Genética , Técnicas de Transferencia Nuclear , Células Madre Pluripotentes/metabolismo , Animales , Humanos , Células Madre Pluripotentes/citología
10.
Cell ; 152(3): 642-54, 2013 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-23333102

RESUMEN

Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence, and reprogramming.


Asunto(s)
Ensamble y Desensamble de Cromatina , Cromatina/metabolismo , Epigénesis Genética , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Núcleo Celular , Senescencia Celular , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Especificidad de Órganos
11.
Cell ; 153(5): 1149-63, 2013 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-23664763

RESUMEN

Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.


Asunto(s)
Células Madre Embrionarias/metabolismo , Epigénesis Genética , Transcripción Genética , Acetilación , Diferenciación Celular , Cromatina/química , Cromatina/metabolismo , Metilación de ADN , Elementos de Facilitación Genéticos , Histonas/metabolismo , Humanos , Metilación
13.
Mol Cell ; 74(5): 951-965.e13, 2019 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-31047794

RESUMEN

RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are key regulators of gene expression, but their joint functions in coordinating cell fate decisions are poorly understood. Here we show that the expression and activity of the RBP TDP-43 and the long isoform of the lncRNA Neat1, the scaffold of the nuclear compartment "paraspeckles," are reciprocal in pluripotent and differentiated cells because of their cross-regulation. In pluripotent cells, TDP-43 represses the formation of paraspeckles by enhancing the polyadenylated short isoform of Neat1. TDP-43 also promotes pluripotency by regulating alternative polyadenylation of transcripts encoding pluripotency factors, including Sox2, which partially protects its 3' UTR from miR-21-mediated degradation. Conversely, paraspeckles sequester TDP-43 and other RBPs from mRNAs and promote exit from pluripotency and embryonic patterning in the mouse. We demonstrate that cross-regulation between TDP-43 and Neat1 is essential for their efficient regulation of a broad network of genes and, therefore, of pluripotency and differentiation.


Asunto(s)
Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Células Madre Embrionarias de Ratones/metabolismo , ARN Largo no Codificante/genética , Animales , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones , MicroARNs/genética , Células Madre Pluripotentes/metabolismo , Poliadenilación/genética , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
14.
Nat Rev Genet ; 21(10): 581-596, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32839576

RESUMEN

In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.


Asunto(s)
Enfermedad/genética , Genética/tendencias , Genoma Humano , Estudio de Asociación del Genoma Completo , Genómica/tendencias , Humanos
15.
Cell ; 145(6): 875-89, 2011 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-21663792

RESUMEN

Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells.


Asunto(s)
Diferenciación Celular , Células Madre Embrionarias/citología , Regulación del Desarrollo de la Expresión Génica , Estratos Germinativos/citología , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Proteínas de Homeodominio/metabolismo , Ratones , Proteína Homeótica Nanog , Células Madre Pluripotentes/citología
16.
Cell ; 144(3): 439-52, 2011 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-21295703

RESUMEN

The developmental potential of human pluripotent stem cells suggests that they can produce disease-relevant cell types for biomedical research. However, substantial variation has been reported among pluripotent cell lines, which could affect their utility and clinical safety. Such cell-line-specific differences must be better understood before one can confidently use embryonic stem (ES) or induced pluripotent stem (iPS) cells in translational research. Toward this goal we have established genome-wide reference maps of DNA methylation and gene expression for 20 previously derived human ES lines and 12 human iPS cell lines, and we have measured the in vitro differentiation propensity of these cell lines. This resource enabled us to assess the epigenetic and transcriptional similarity of ES and iPS cells and to predict the differentiation efficiency of individual cell lines. The combination of assays yields a scorecard for quick and comprehensive characterization of pluripotent cell lines.


Asunto(s)
Metilación de ADN , Células Madre Embrionarias/fisiología , Perfilación de la Expresión Génica/normas , Células Madre Pluripotentes Inducidas/fisiología , Diferenciación Celular , Línea Celular , Células Madre Embrionarias/citología , Humanos , Células Madre Pluripotentes Inducidas/citología
17.
Nature ; 584(7819): 102-108, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32728215

RESUMEN

During ontogeny, proliferating cells become restricted in their fate through the combined action of cell-type-specific transcription factors and ubiquitous epigenetic machinery, which recognizes universally available histone residues or nucleotides in a context-dependent manner1,2. The molecular functions of these regulators are generally well understood, but assigning direct developmental roles to them is hampered by complex mutant phenotypes that often emerge after gastrulation3,4. Single-cell RNA sequencing and analytical approaches have explored this highly conserved, dynamic period across numerous model organisms5-8, including mouse9-18. Here we advance these strategies using a combined zygotic perturbation and single-cell RNA-sequencing platform in which many mutant mouse embryos can be assayed simultaneously, recovering robust  morphological and transcriptional information across a panel of ten essential regulators. Deeper analysis of central Polycomb repressive complex (PRC) 1 and 2 components indicates substantial cooperativity, but distinguishes a dominant role for PRC2 in restricting the germline. Moreover, PRC mutant phenotypes emerge after gross epigenetic and transcriptional changes within the initial conceptus prior to gastrulation. Our experimental framework may eventually lead to a fully quantitative view of how cellular diversity emerges using an identical genetic template and from a single totipotent cell.


Asunto(s)
Epigénesis Genética , Gástrula/embriología , Gástrula/metabolismo , Gastrulación/genética , Animales , Linaje de la Célula , Femenino , Gástrula/citología , Regulación del Desarrollo de la Expresión Génica , Masculino , Ratones , Mutación , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Análisis de la Célula Individual , Transcripción Genética
18.
Trends Genet ; 38(7): 676-707, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35504755

RESUMEN

In 1925, 5-methylcytosine was first reported in bacteria. However, its biological importance was not intuitive for several decades. After this initial lag, the ubiquitous presence of this methylated base emerged across all domains of life and revealed a range of essential biological functions. Today, we are armed with the knowledge of the key factors that establish, maintain, and remove DNA methylation and have access to a staggering and rapidly growing number of base-resolution methylation maps. Despite this, several fundamental details about the precise role and interpretation of DNA methylation patterns remain under investigation. Here, we review the field of DNA methylation from its beginning to present day, with an emphasis on findings in mammalian systems, and point the reader to select experiments that form the foundation of this field.


Asunto(s)
5-Metilcitosina , Metilación de ADN , Animales , Metilación de ADN/genética , Mamíferos
19.
Bioinformatics ; 40(3)2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38485699

RESUMEN

MOTIVATION: Local alignments of query sequences in large databases represent a core part of metagenomic studies and facilitate homology search. Following the development of NCBI Blast, many applications aimed to provide faster and equally sensitive local alignment frameworks. Most applications focus on protein alignments, while only few also facilitate DNA-based searches. None of the established programs allow searching DNA sequences from bisulfite sequencing experiments commonly used for DNA methylation profiling, for which specific alignment strategies need to be implemented. RESULTS: Here, we introduce Lambda3, a new version of the local alignment application Lambda. Lambda3 is the first solution that enables the search of protein, nucleotide as well as bisulfite-converted nucleotide query sequences. Its protein mode achieves comparable performance to that of the highly optimized protein alignment application Diamond, while the nucleotide mode consistently outperforms established local nucleotide aligners. Combined, Lambda3 presents a universal local alignment framework that enables fast and sensitive homology searches for a wide range of use-cases. AVAILABILITY AND IMPLEMENTATION: Lambda3 is free and open-source software publicly available at https://github.com/seqan/lambda/.


Asunto(s)
Algoritmos , Programas Informáticos , Sulfitos , Alineación de Secuencia , Proteínas
20.
Cell ; 143(7): 1084-96, 2010 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-21183072

RESUMEN

Epigenetic information can be inherited through the mammalian germline and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Offspring of males fed a low-protein diet exhibited elevated hepatic expression of many genes involved in lipid and cholesterol biosynthesis and decreased levels of cholesterol esters, relative to the offspring of males fed a control diet. Epigenomic profiling of offspring livers revealed numerous modest (∼20%) changes in cytosine methylation depending on paternal diet, including reproducible changes in methylation over a likely enhancer for the key lipid regulator Ppara. These results, in conjunction with recent human epidemiological data, indicate that parental diet can affect cholesterol and lipid metabolism in offspring and define a model system to study environmental reprogramming of the heritable epigenome.


Asunto(s)
Metilación de ADN , Dieta con Restricción de Proteínas , Impresión Genómica , Metabolismo de los Lípidos , Animales , Vías Biosintéticas , Colesterol/biosíntesis , Citosina/metabolismo , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Hígado/metabolismo , Masculino , Ratones
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