RESUMEN
Combining moral philosophy with sociological theory to build on themes introduced in Hall and Lamont's Successful Societies (2009), the paper outlines a distinctive perspective. It holds that a necessary condition of successful societies is that decision-makers base their decisions on a high level of attentiveness (concern and comprehension) towards subjectively valued and morally legitimate forms of life. Late modern societies consist of a plurality of forms of life, each providing grounds for what Alasdair MacIntyre has called internal goods-valued and morally valuable practices. The status of such goods is examined, and distinctions are drawn between their manifest and latent, and transposable and situationally specific, characteristics. We integrate this refined idea of internal goods into a developed conception of habitus that is both morally informed and situationally embedded. The sociological approach of strong structuration theory (SST) is employed to demonstrate how this conception of habitus can guide the critique of decision-making that damages internal goods. We identify the most pervasive and invidious forms of damaging decision-making in contemporary societies as those involving excessive forms of instrumental reasoning. We argue that our developed conception of habitus, anchored in the collectively valued practices of specific worlds, can be a powerful focus for resistance. Accounts of scholarship in higher education and of the white working class in America illustrate the specificities of singular, particular, social worlds and illuminate critical challenges raised by the perspective we advocate.
Asunto(s)
Toma de Decisiones en la Organización , Sociedades/organización & administración , Atención , Educación , Humanos , Modelos Teóricos , Principios Morales , Filosofía , Clase Social , Sociología , Estados UnidosRESUMEN
Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi-induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. Also see the video abstract here.
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Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Animales , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Humanos , Masculino , Mutación , Neoplasias/enzimología , Transducción de Señal/efectos de los fármacosRESUMEN
The nucleosome core particle is the first stage of DNA packaging in virtually all eukaryotes. It both organises nuclear DNA and protects it from adventitious binding of transcription factors and the consequent deregulation of gene expression. Both properties are essential to allow the genome expansion characteristic of complex eukaryotes. The nucleosome is a flexible structure in vivo, allowing selective relaxation of its intrinsically inhibitory effects in response to external signals. Structural changes are brought about by dedicated remodelling enzymes and by posttranslational modifications of the core histones. Histone modifications occasionally alter nucleosome structure directly, but their more usual roles are to act as receptors on the nucleosome surface that are recognised by specific protein domains. The bound proteins, in turn, affect nucleosome structure and function. This strategy enormously expands the signalling capacity of the nucleosome and its ability to influence both the initiation and elongation stages of transcription. The enzymes responsible for placing and removing histone modifications, and the modification-binding proteins themselves, are ubiquitous, numerous and conserved amongst eukaryotes. Like the nucleosome, they date back to the earliest eukaryotes and may have played integral and essential roles in eukaryotic evolution. The present properties and epigenetic functions of the nucleosome reflect its evolutionary past and the selective pressures to which it has responded and can be better understood in this context. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.
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ADN/metabolismo , Histonas/metabolismo , Nucleosomas/metabolismo , Procesamiento Proteico-Postraduccional , Transducción de Señal/genética , Acetilación , Animales , Evolución Biológica , ADN/genética , Epigénesis Genética , Histonas/genética , Humanos , Nucleosomas/ultraestructura , Estructura Terciaria de Proteína , Transcripción GenéticaRESUMEN
This review examines the proposition that the nucleosome, in addition to its role as a DNA packaging device, is a signaling module through which changing environmental and metabolic conditions can influence genomic functions. The role of enzyme-catalyzed post-translational modifications of the core histones is critically assessed, leading to the conclusion that they play varied, often crucial and sometimes causative roles in this signaling process.
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Epigénesis Genética , Nucleosomas/genética , Transducción de Señal , Animales , ADN/química , ADN/genética , ADN/metabolismo , Histonas/metabolismo , Humanos , Nucleosomas/metabolismoRESUMEN
BACKGROUND: Using metaphase spreads from human lymphoblastoid cell lines, we previously showed how immunofluorescence microscopy could define the distribution of histone modifications across metaphase chromosomes. We showed that different histone modifications gave consistent and clearly defined immunofluorescent banding patterns. However, it was not clear to what extent these higher level distributions were influenced by long-term growth in culture, or by the specific functional associations of individual histone modifications. RESULTS: Metaphase chromosome spreads from human lymphocytes stimulated to grow in short-term culture, were immunostained with antibodies to histone H3 mono- or tri-methylated at lysine 4 (H3K4me1, H3K4me3). Chromosomes were identified on the basis of morphology and reverse DAPI (rDAPI) banding. Both antisera gave the same distinctive immunofluorescent staining pattern, with unstained heterochromatic regions and a banded distribution along the chromosome arms. Karyotypes were prepared, showing the reproducibility of banding between sister chromatids, homologue pairs and from one metaphase spread to another. At the light microscope level, we detect no difference between the banding patterns along chromosomes from primary lymphocytes and lymphoblastoid cell lines adapted to long-term growth in culture. CONCLUSIONS: The distribution of H3K4me3 is the same across metaphase chromosomes from human primary lymphocytes and LCL, showing that higher level distribution is not altered by immortalization or long-term culture. The two modifications H3K4me1 (enriched in gene enhancer regions) and H3K4me3 (enriched in gene promoter regions) show the same distributions across human metaphase chromosomes, showing that functional differences do not necessarily cause modifications to differ in their higher-level distributions.
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Cromosomas Humanos , Histonas/genética , Histonas/metabolismo , Linfocitos/metabolismo , Metafase , Línea Celular , Bandeo Cromosómico , Humanos , Lisina , Metilación , Isoformas de ProteínasRESUMEN
Chromatin immunoprecipitation (ChIP) defines the genomic distribution of proteins and their modifications but is limited by the cell numbers required (ideally >10(7)). Here we describe a protocol that uses carrier chromatin and PCR, 'carrier' ChIP (CChIP), to permit analysis of as few as 100 cells. We assayed histone modifications at key regulator genes (such as Nanog, Pou5f1 (also known as Oct4) and Cdx2) by CChIP in mouse embryonic stem (ES) cells and in inner cell mass (ICM) and trophectoderm of cultured blastocysts. Activating and silencing modifications (H4 acetylation and H3K9 methylation) mark active and silent promoters as predicted, and we find close correlation between values derived from CChIP (1,000 ES cells) and conventional ChIP (5 x 10(7) ES cells). Studies on genes silenced in both ICM and ES cells (Cdx2, Cfc1, Hhex and Nkx2-2, also known as Nkx) show that the intensity of silencing marks is relatively diminished in ES cells, indicating a possible relaxation of some components of silencing on adaptation to culture.
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Blastocisto/metabolismo , Inmunoprecipitación de Cromatina/métodos , Epigénesis Genética , Animales , Blastocisto/citología , Recuento de Células , Línea Celular , Silenciador del Gen , Genes Reguladores , Histonas/metabolismo , Proteína Homeobox Nkx-2.2 , Ratones , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Células Madre/citología , Células Madre/metabolismoRESUMEN
Human kinetochores are transcriptionally active, producing very low levels of transcripts of the underlying alpha-satellite DNA. However, it is not known whether kinetochores can tolerate acetylated chromatin and the levels of transcription that are characteristic of housekeeping genes, or whether kinetochore-associated 'centrochromatin', despite being transcribed at a low level, is essentially a form of repressive chromatin. Here, we have engineered two types of acetylated chromatin within the centromere of a synthetic human artificial chromosome. Tethering a minimal NF-κB p65 activation domain within kinetochore-associated chromatin produced chromatin with high levels of histone H3 acetylated on lysine 9 (H3K9ac) and an ~10-fold elevation in transcript levels, but had no substantial effect on kinetochore assembly or function. By contrast, tethering the herpes virus VP16 activation domain produced similar modifications in the chromatin but resulted in an ~150-fold elevation in transcripts, approaching the level of transcription of an endogenous housekeeping gene. This rapidly inactivated kinetochores, causing a loss of assembled CENP-A and blocking further CENP-A assembly. Our data reveal that functional centromeres in vivo show a remarkable plasticity--kinetochores tolerate profound changes to their chromatin environment, but appear to be critically sensitive to the level of centromeric transcription.
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Centrómero/metabolismo , Epigénesis Genética , Histonas/metabolismo , Cinetocoros/fisiología , Acetilación , Autoantígenos/metabolismo , Línea Celular , Proteína A Centromérica , Cromatina/química , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas Artificiales Humanos , Proteína Vmw65 de Virus del Herpes Simple/genética , Histonas/química , Humanos , Cinetocoros/química , Lisina/metabolismo , Proteínas Recombinantes de Fusión , Factor de Transcripción ReIA/genéticaRESUMEN
The nucleosome surface is decorated with an array of enzyme-catalysed modifications on histone tails. These modifications have well-defined roles in a variety of ongoing chromatin functions, often by acting as receptors for non-histone proteins, but their longer-term effects are less clear. Here, an attempt is made to define how histone modifications operate as part of a predictive and heritable epigenetic code that specifies patterns of gene expression through differentiation and development.
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Epigénesis Genética , Regulación del Desarrollo de la Expresión Génica , Modelos Genéticos , Nucleosomas/genética , Transcripción Genética , Animales , Cromatina/genética , Histonas/genética , MetilaciónRESUMEN
The current study investigated transcriptional distortion in prostate cancer cells using the vitamin D receptor (VDR) as a tool to examine how epigenetic events driven by corepressor binding and CpG methylation lead to aberrant gene expression. These relationships were investigated in the non-malignant RWPE-1 cells that were 1α,25(OH)(2)D(3) responsive (RWPE-1) and malignant cell lines that were 1α,25(OH)(2)D(3) partially responsive (RWPE-2) and resistant (PC-3). These studies revealed that selective attenuation and repression of VDR transcriptional responses in the cancer cell lines reflected their loss of antiproliferative sensitivity. This was evident in VDR target genes including VDR, CDKN1A (encodes p21( (waf1/cip1) )) and GADD45A; NCOR1 knockdown alleviated this malignant transrepression. ChIP assays in RWPE-1 and PC-3 cells revealed that transrepression of CDKN1A was associated with increased NCOR1 enrichment in response to 1α,25(OH)(2)D(3) treatment. These findings supported the concept that retained and increased NCOR1 binding, associated with loss of H3K9ac and increased H3K9me2, may act as a beacon for the initiation and recruitment of DNA methylation. Overexpressed histone methyltransferases (KMTs) were detectable in a wide panel of prostate cancer cell lines compared with RWPE-1 and suggested that generation of H3K9me2 states would be favored. Cotreatment of cells with the KMT inhibitor, chaetocin, increased 1α,25(OH)(2)D(3)-mediated induction of CDKN1A expression supporting a role for this event to disrupt CDKN1A regulation. Parallel surveys in PC-3 cells of CpG methylation around the VDR binding regions on CDKN1A revealed altered basal and VDR-regulated DNA methylation patterns that overlapped with VDR-induced recruitment of NCOR1 and gene transrepression. Taken together, these findings suggest that sustained corepressor interactions with nuclear-resident transcription factors may inappropriately transform transient-repressive histone states into more stable and repressive DNA methylation events.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Metilación de ADN , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Co-Represor 1 de Receptor Nuclear/metabolismo , Neoplasias de la Próstata/genética , Receptores de Calcitriol/metabolismo , Apoptosis/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Calcitriol/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inmunoprecipitación de Cromatina , Epigénesis Genética , Humanos , Masculino , Co-Represor 1 de Receptor Nuclear/genética , Regiones Promotoras Genéticas/genética , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Calcitriol/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de SeñalRESUMEN
In non-malignant RWPE-1 prostate epithelial cells signaling by the nuclear receptor Vitamin D Receptor (VDR, NR1I1) induces cell cycle arrest through targets including CDKN1A (encodes p21((waf1/cip1))). VDR dynamically induced individual histone modification patterns at three VDR binding sites (R1, 2, 3) on the CDKN1A promoter. The magnitude of these modifications was specific to each phase of the cell cycle. For example, H3K9ac enrichment occurred rapidly only at R2, whereas parallel accumulation of H3K27me3 occurred at R1; these events were significantly enriched in G(1) and S phase cells, respectively. The epigenetic events appeared to allow VDR actions to combine with p53 to enhance p21((waf1/cip1)) activation further. In parallel, VDR binding to the MCM7 gene induced H3K9ac enrichment associated with rapid mRNA up-regulation to generate miR-106b and consequently regulate p21((waf1/cip1)) expression. We conclude that VDR binding site- and promoter-specific patterns of histone modifications combine with miRNA co-regulation to form a VDR-regulated feed-forward loop to control p21((waf1/cip1)) expression and cell cycle arrest. Dissection of this feed-forward loop in a non-malignant prostate cell system illuminates mechanisms of sensitivity and therefore possible resistance in prostate and other VDR responsive cancers.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Epigénesis Genética , Próstata/metabolismo , Receptores de Calcitriol/metabolismo , Animales , Calcitriol/farmacología , Ciclo Celular/efectos de los fármacos , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Retroalimentación Fisiológica , Histonas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Regiones Promotoras Genéticas , Próstata/efectos de los fármacos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismoRESUMEN
In human health and disease the choreographed actions of a wide armory of transcription factors govern the regulated expression of coding and nonprotein coding genes. These actions are central to human health and are evidently aberrant in cancer. Central components of regulated gene expression are a variety of epigenetic mechanisms that include histone modifications. The post-translational modifications of histones are widespread and diverse, and appear to be spatial--temporally regulated in a highly intricate manner. The true functional consequences of these patterns of regulation are still emerging. Correlative evidence supports the idea that these patterns are distorted in malignancy on both a genome-wide and a discrete gene loci level. These patterns of distortion also often reflect the altered expression of the enzymes that control these histone states. Similarly gene expression patterns also appear to reflect a correlation with altered histone modifications at both the candidate loci and genome-wide level. Clarity is emerging in resolving these relationships between histone modification status and gene expression -patterns. For example, altered transcription factor interactions with the key co-activator and co-repressors, which in turn marshal many of the histone-modifying enzymes, may distort regulation of histone modifications at specific gene loci. In turn these aberrant transcriptional processes can trigger other altered epigenetic events such as DNA methylation and underline the aberrant and specific gene expression patterns in cancer. Considered in this manner, altered expression and recruitment of histone-modifying enzymes may underline the distortion to transcriptional responsiveness observed in malignancy. Insight from understanding these processes addresses the challenge of targeted epigenetic therapies in cancer.
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Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Neoplasias/genética , Neoplasias/patología , Animales , Humanos , Neoplasias/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
This article makes a contribution to the on-going debates about universalism and cultural relativism from the perspective of sociology. We argue that bioethics has a universal range because it relates to three shared human characteristics,--human vulnerability, institutional precariousness and scarcity of resources. These three components of our argument provide support for a related notion of 'weak foundationalism' that emphasizes the universality and interrelatedness of human experience, rather than their cultural differences. After presenting a theoretical position on vulnerability and human rights, we draw on recent criticism of this approach in order to paint a more nuanced picture. We conclude that the dichotomy between universalism and cultural relativism has some conceptual merit, but it also has obvious limitations when we consider the political economy of health and its impact on social inequality.
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Diversidad Cultural , Derechos Humanos , Poblaciones Vulnerables , Bioética , Humanos , InternacionalidadRESUMEN
The article examines the merits of both human rights and citizenship as systems to protect vulnerable individuals. The idea of vulnerability is presented as a more reliable concept than the dignity of the individual in comparative research. The body is basic to vulnerability.
RESUMEN
Previous reports showed that embryonic stem (ES) cells contain hyperdynamic and globally transcribed chromatin-properties that are important for ES cell pluripotency and differentiation. Here, we demonstrate a role for undifferentiated embryonic cell transcription factor 1 (UTF1) in regulating ES cell chromatin structure. Using chromatin immunoprecipitation-on-chip analysis, we identified >1,700 UTF1 target genes that significantly overlap with previously identified Nanog, Oct4, Klf-4, c-Myc, and Rex1 targets. Gene expression profiling showed that UTF1 knock down results in increased expression of a large set of genes, including a significant number of UTF1 targets. UTF1 knock down (KD) ES cells are, irrespective of the increased expression of several self-renewal genes, Leukemia inhibitory factor (LIF) dependent. However, UTF1 KD ES cells are perturbed in their differentiation in response to dimethyl sulfoxide (DMSO) or after LIF withdrawal and display increased colony formation. UTF1 KD ES cells display extensive chromatin decondensation, reflected by a dramatic increase in nucleosome release on micrococcal nuclease (MNase) treatment and enhanced MNase sensitivity of UTF1 target genes in UTF1 KD ES cells. Summarizing, our data show that UTF1 is a key chromatin component in ES cells, preventing ES cell chromatin decondensation, and aberrant gene expression; both essential for proper initiation of lineage-specific differentiation of ES cells.
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Cromatina/metabolismo , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica/genética , Transactivadores/metabolismo , Animales , Southern Blotting , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Línea Celular , Línea Celular Tumoral , Cromatina/genética , Inmunoprecipitación de Cromatina , Proteínas Cromosómicas no Histona , Regulación de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Ratones , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genética , Transactivadores/genéticaRESUMEN
Histone acetylation is a key modification that regulates chromatin accessibility. Here we show that treatment with butyrate or other histone deacetylase (HDAC) inhibitors does not induce histone hyperacetylation in metaphase-arrested HeLa cells. When compared to similarly treated interphase cells, acetylation levels are significantly decreased in all four core histones and at all individual sites examined. However, the extent of the decrease varies, ranging from only slight reduction at H3K23 and H4K12 to no acetylation at H3K27 and barely detectable acetylation at H4K16. Our results show that the bulk effect is not due to increased or butyrate-insensitive HDAC activity, though these factors may play a role with some individual sites. We conclude that the lack of histone acetylation during mitosis is primarily due to changes in histone acetyltransferases (HATs) or changes in chromatin. The effects of protein phosphatase inhibitors on histone acetylation in cell lysates suggest that the reduced ability of histones to become acetylated in mitotic cells depends on protein phosphorylation.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Histonas/metabolismo , Mitosis/efectos de los fármacos , Acetilación , Butiratos/farmacología , Cromatina/fisiología , Células HeLa/efectos de los fármacos , Células HeLa/metabolismo , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional , Transducción de SeñalRESUMEN
Chromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10-50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1-5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.
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Cromosomas/genética , Epigénesis Genética , Código de Histonas/genética , Procesamiento Proteico-Postraduccional/genética , Acetilación , Ciclo Celular , Cromatina/genética , Células HeLa , Histonas/genética , Humanos , Lisina , Metilación , Mitosis/genética , Nucleosomas/genéticaRESUMEN
The genetic code epitomises simplicity, near universality and absolute predictive power. By contrast, epigenetic information, in the form of histone modifications, is characterised by complexity, diversity and an overall tendency to respond to changes in genomic function rather than to predict them. Perhaps the transient changes in histone modifications involved in intranuclear signalling and ongoing chromatin functions mask stable, predictive modifications that lie beneath. The current rapid progress in unravelling the diversity and complexity of epigenetic information might eventually reveal an underlying histone or epigenetic code. But whether it does or not, it will certainly provide unprecedented opportunities, both for understanding how the genome responds to environmental and metabolic change and for manipulating its activities for experimental and therapeutic benefit.
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Epigénesis Genética , Histonas/genética , Receptor Cross-Talk , Transducción de Señal , Cromatina/metabolismo , Genoma , Histonas/metabolismo , Modelos Biológicos , Procesamiento Proteico-PostraduccionalRESUMEN
Dosage compensation in mammals involves silencing of one X chromosome in XX females and requires expression, in cis, of Xist RNA. The X to be inactivated is randomly chosen in cells of the inner cell mass (ICM) at the blastocyst stage of development. Embryonic stem (ES) cells derived from the ICM of female mice have two active X chromosomes, one of which is inactivated as the cells differentiate in culture, providing a powerful model system to study the dynamics of X inactivation. Using microarrays to assay expression of X-linked genes in undifferentiated female and male mouse ES cells, we detect global up-regulation of expression (1.4- to 1.6-fold) from the active X chromosomes, relative to autosomes. We show a similar up-regulation in ICM from male blastocysts grown in culture. In male ES cells, up-regulation reaches 2-fold after 2-3 weeks of differentiation, thereby balancing expression between the single X and the diploid autosomes. We show that silencing of X-linked genes in female ES cells occurs on a gene-by-gene basis throughout differentiation, with some genes inactivating early, others late, and some escaping altogether. Surprisingly, by allele-specific analysis in hybrid ES cells, we also identified a subgroup of genes that are silenced in undifferentiated cells. We propose that X-linked genes are silenced in female ES cells by spreading of Xist RNA through the X chromosome territory as the cells differentiate, with silencing times for individual genes dependent on their proximity to the Xist locus.
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Compensación de Dosificación (Genética)/genética , Silenciador del Gen , Genes Ligados a X/genética , Regulación hacia Arriba/genética , Alelos , Animales , Diferenciación Celular , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Inactivación del Cromosoma X/genéticaRESUMEN
The tails of the four core histones are exposed on the nucleosome surface, where they are subject to a variety of enzyme-catalyzed, post-translational modifications. Modifications, singly or in combination, provide a source of information that can be used for signal transduction during ongoing processes, such as transcription, or as heritable epigenetic marks. A nomenclature is presented that allows patterns of histone modification to be clearly and unambiguously specified and that should facilitate discussion of their functional roles.