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1.
Nature ; 518(7539): 317-30, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25693563

RESUMO

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.


Assuntos
Epigênese Genética/genética , Epigenômica , Genoma Humano/genética , Sequência de Bases , Linhagem da Célula/genética , Células Cultivadas , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Cromossomos Humanos/química , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Metilação de DNA , Conjuntos de Dados como Assunto , Elementos Facilitadores Genéticos/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Especificidade de Órgãos/genética , RNA/genética , Valores de Referência
2.
Nature ; 515(7527): 402-5, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25409831

RESUMO

Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.


Assuntos
Cromatina/química , Cromatina/genética , Período de Replicação do DNA , DNA/biossíntese , Animais , Compartimento Celular , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA/genética , Genoma/genética , Heterocromatina/química , Heterocromatina/genética , Heterocromatina/metabolismo , Humanos , Camundongos , Especificidade de Órgãos , Fatores de Tempo
3.
Nature ; 515(7527): 365-70, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25409825

RESUMO

The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.


Assuntos
Sequência Conservada/genética , Evolução Molecular , Mamíferos/genética , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Pegada de DNA , Regulação da Expressão Gênica no Desenvolvimento/genética , Redes Reguladoras de Genes/genética , Humanos , Camundongos
4.
Nature ; 489(7414): 75-82, 2012 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-22955617

RESUMO

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.


Assuntos
Cromatina/genética , Cromatina/metabolismo , DNA/genética , Enciclopédias como Assunto , Genoma Humano/genética , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico/genética , Pegada de DNA , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Desoxirribonuclease I/metabolismo , Evolução Molecular , Genômica , Humanos , Taxa de Mutação , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição , Transcrição Gênica
5.
Nature ; 489(7414): 83-90, 2012 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-22955618

RESUMO

Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.


Assuntos
Pegada de DNA , DNA/genética , Enciclopédias como Assunto , Genoma Humano/genética , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Desoxirribonuclease I/metabolismo , Impressão Genômica , Genômica , Humanos , Polimorfismo de Nucleotídeo Único/genética , Sítio de Iniciação de Transcrição
6.
Nature ; 471(7339): 480-5, 2011 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-21179089

RESUMO

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.


Assuntos
Cromatina/genética , Cromatina/metabolismo , Drosophila melanogaster/genética , Animais , Linhagem Celular , Imunoprecipitação da Cromatina , Proteínas Cromossômicas não Histona/análise , Proteínas Cromossômicas não Histona/metabolismo , Desoxirribonuclease I/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/crescimento & desenvolvimento , Éxons/genética , Regulação da Expressão Gênica/genética , Genes de Insetos/genética , Genoma de Inseto/genética , Histonas/química , Histonas/metabolismo , Masculino , Anotação de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Complexo Repressor Polycomb 1 , RNA/análise , RNA/genética , Análise de Sequência , Transcrição Gênica/genética
7.
Genome Res ; 22(9): 1680-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22955980

RESUMO

CTCF is a ubiquitously expressed regulator of fundamental genomic processes including transcription, intra- and interchromosomal interactions, and chromatin structure. Because of its critical role in genome function, CTCF binding patterns have long been assumed to be largely invariant across different cellular environments. Here we analyze genome-wide occupancy patterns of CTCF by ChIP-seq in 19 diverse human cell types, including normal primary cells and immortal lines. We observed highly reproducible yet surprisingly plastic genomic binding landscapes, indicative of strong cell-selective regulation of CTCF occupancy. Comparison with massively parallel bisulfite sequencing data indicates that 41% of variable CTCF binding is linked to differential DNA methylation, concentrated at two critical positions within the CTCF recognition sequence. Unexpectedly, CTCF binding patterns were markedly different in normal versus immortal cells, with the latter showing widespread disruption of CTCF binding associated with increased methylation. Strikingly, this disruption is accompanied by up-regulation of CTCF expression, with the result that both normal and immortal cells maintain the same average number of CTCF occupancy sites genome-wide. These results reveal a tight linkage between DNA methylation and the global occupancy patterns of a major sequence-specific regulatory factor.


Assuntos
Metilação de DNA , Proteínas Repressoras/metabolismo , Sítios de Ligação/genética , Fator de Ligação a CCCTC , Linhagem Celular , Imunoprecipitação da Cromatina , Análise por Conglomerados , Ilhas de CpG , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
8.
Proc Natl Acad Sci U S A ; 107(1): 139-44, 2010 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-19966280

RESUMO

Faithful transmission of genetic material to daughter cells involves a characteristic temporal order of DNA replication, which may play a significant role in the inheritance of epigenetic states. We developed a genome-scale approach--Repli Seq--to map temporally ordered replicating DNA using massively parallel sequencing and applied it to study regional variation in human DNA replication time across multiple human cell types. The method requires as few as 8,000 cytometry-fractionated cells for a single analysis, and provides high-resolution DNA replication patterns with respect to both cell-cycle time and genomic position. We find that different cell types exhibit characteristic replication signatures that reveal striking plasticity in regional replication time patterns covering at least 50% of the human genome. We also identified autosomal regions with marked biphasic replication timing that include known regions of monoallelic expression as well as many previously uncharacterized domains. Comparison with high-resolution genome-wide profiles of DNaseI sensitivity revealed that DNA replication typically initiates within foci of accessible chromatin comprising clustered DNaseI hypersensitive sites, and that replication time is better correlated with chromatin accessibility than with gene expression. The data collectively provide a unique, genome-wide picture of the epigenetic compartmentalization of the human genome and suggest that cell-lineage specification involves extensive reprogramming of replication timing patterns.


Assuntos
Replicação do DNA , DNA/genética , Análise de Sequência de DNA , Animais , Linhagem Celular , Cromatina/química , Cromatina/genética , Bases de Dados Genéticas , Epigênese Genética , Perfilação da Expressão Gênica , Genoma Humano , Humanos
9.
BMC Genet ; 7: 41, 2006 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-16817970

RESUMO

BACKGROUND: X chromosome inactivation (XCI) is that aspect of mammalian dosage compensation that brings about equivalence of X-linked gene expression between females and males by inactivating one of the two X chromosomes (Xi) in normal female cells, leaving them with a single active X (Xa) as in male cells. In cells with more than two X's, but a diploid autosomal complement, all X's but one, Xa, are inactivated. This phenomenon is commonly thought to suggest 1) that normal development requires a ratio of one Xa per diploid autosomal set, and 2) that an early event in XCI is the marking of one X to be active, with remaining X's becoming inactivated by default. RESULTS: Triploids provide a test of these ideas because the ratio of one Xa per diploid autosomal set cannot be achieved, yet this abnormal ratio should not necessarily affect the one-Xa choice mechanism for XCI. Previous studies of XCI patterns in murine triploids support the single-Xa model, but human triploids mostly have two-Xa cells, whether they are XXX or XXY. The XCI patterns we observe in fibroblast cultures from different XXX human triploids suggest that the two-Xa pattern of XCI is selected for, and may have resulted from rare segregation errors or Xi reactivation. CONCLUSION: The initial X inactivation pattern in human triploids, therefore, is likely to resemble the pattern that predominates in murine triploids, i.e., a single Xa, with the remaining X's inactive. Furthermore, our studies of XIST RNA accumulation and promoter methylation suggest that the basic features of XCI are normal in triploids despite the abnormal X:autosome ratio.


Assuntos
Cromossomos Humanos X , Poliploidia , Inativação do Cromossomo X , Células Cultivadas , Cromossomos Humanos , Células Clonais , Metilação de DNA , DNA Satélite/análise , Feminino , Fibroblastos/citologia , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Masculino , RNA Longo não Codificante , RNA não Traduzido/análise
10.
BMC Biol ; 2: 21, 2004 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-15377381

RESUMO

BACKGROUND: In mammals, there is evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with modification complexes that can deacetylate and/or methylate nucleosomes in the proximity of methylated DNA. We examined this idea for the X chromosome by studying histone modifications on the X chromosome in normal cells and in cells from patients with ICF syndrome (Immune deficiency, Centromeric region instability, and Facial anomalies syndrome). In normal cells the inactive X has characteristic silencing type histone modification patterns and the CpG islands of genes subject to X inactivation are hypermethylated. In ICF cells, however, genes subject to X inactivation are hypomethylated on the inactive X due to mutations in the DNA methyltransferase (DNMT3B) genes. Therefore, if DNA methylation is upstream of histone modification, the histones on the inactive X in ICF cells should not be modified to a silent form. In addition, we determined whether a specific methyl-CpG binding protein, MeCP2, is necessary for the inactive X histone modification pattern by studying Rett syndrome cells which are deficient in MeCP2 function. RESULTS: We show here that the inactive X in ICF cells, which appears to be hypomethylated at all CpG islands, exhibits normal histone modification patterns. In addition, in Rett cells with no functional MeCP2 methyl-CpG binding protein, the inactive X also exhibits normal histone modification patterns. CONCLUSIONS: These data suggest that DNA methylation and the associated methyl-DNA binding proteins may not play a critical role in determining histone modification patterns on the mammalian inactive X chromosome at the sites analyzed.


Assuntos
Cromossomos Humanos X/genética , Ilhas de CpG/genética , Histonas/metabolismo , Síndromes de Imunodeficiência/genética , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Inativação do Cromossomo X , Células Cultivadas , Metilação de DNA , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Síndromes de Imunodeficiência/metabolismo , Proteína 2 de Ligação a Metil-CpG/deficiência , Proteína 2 de Ligação a Metil-CpG/metabolismo , Síndrome de Rett/metabolismo , Síndrome de Rett/patologia
11.
Cell Rep ; 12(7): 1184-95, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26257180

RESUMO

Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5%) of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites.


Assuntos
Metilação de DNA , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Humanos , Ligação Proteica
12.
Artigo em Inglês | MEDLINE | ID: mdl-25972927

RESUMO

BACKGROUND: The brain, spinal cord, and neural retina comprise the central nervous system (CNS) of vertebrates. Understanding the regulatory mechanisms that underlie the enormous cell-type diversity of the CNS is a significant challenge. Whole-genome mapping of DNase I-hypersensitive sites (DHSs) has been used to identify cis-regulatory elements in many tissues. We have applied this approach to the mouse CNS, including developing and mature neural retina, whole brain, and two well-characterized brain regions, the cerebellum and the cerebral cortex. RESULTS: For the various regions and developmental stages of the CNS that we analyzed, there were approximately the same number of DHSs; however, there were many DHSs unique to each CNS region and developmental stage. Many of the DHSs are likely to mark enhancers that are specific to the specific CNS region and developmental stage. We validated the DNase I mapping approach for identification of CNS enhancers using the existing VISTA Browser database and with in vivo and in vitro electroporation of the retina. Analysis of transcription factor consensus sites within the DHSs shows distinct region-specific profiles of transcriptional regulators particular to each region. Clustering developmentally dynamic DHSs in the retina revealed enrichment of developmental stage-specific transcriptional regulators. Additionally, we found reporter gene activity in the retina driven from several previously uncharacterized regulatory elements surrounding the neurodevelopmental gene Otx2. Identification of DHSs shared between mouse and human showed region-specific differences in the evolution of cis-regulatory elements. CONCLUSIONS: Overall, our results demonstrate the potential of genome-wide DNase I mapping to cis-regulatory questions regarding the regional diversity within the CNS. These data represent an extensive catalogue of potential cis-regulatory elements within the CNS that display region and temporal specificity, as well as a set of DHSs common to CNS tissues. Further examination of evolutionary conservation of DHSs between CNS regions and different species may reveal important cis-regulatory elements in the evolution of the mammalian CNS.

13.
Science ; 346(6212): 1007-12, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25411453

RESUMO

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.


Assuntos
Sequência Conservada , DNA/genética , Evolução Molecular , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Desoxirribonuclease I , Genoma Humano , Humanos , Camundongos , Mapeamento por Restrição
14.
Curr Protoc Mol Biol ; Chapter 27: Unit 21.27, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23821440

RESUMO

DNase I-seq is a global and high-resolution method that uses the nonspecific endonuclease DNase I to map chromatin accessibility. These accessible regions, designated as DNase I hypersensitive sites (DHSs), define the regulatory features, (e.g., promoters, enhancers, insulators, and locus control regions) of complex genomes. In this unit, methods are described for nuclei isolation, digestion of nuclei with limiting concentrations of DNase I, and the biochemical fractionation of DNase I hypersensitive sites in preparation for high-throughput sequencing. DNase I-seq is an unbiased and robust method that is not predicated on an a priori understanding of regulatory patterns or chromatin features.


Assuntos
Núcleo Celular/genética , Cromatina/metabolismo , Desoxirribonuclease I/metabolismo , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Sítios de Ligação , Regulação da Expressão Gênica , Biologia Molecular/métodos
15.
Science ; 337(6099): 1190-5, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22955828

RESUMO

Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.


Assuntos
DNA/genética , Doença/genética , Variação Genética , Polimorfismo de Nucleotídeo Único , Elementos Reguladores de Transcrição , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Alelos , Cromatina/metabolismo , Cromatina/ultraestrutura , Doença de Crohn/genética , Desoxirribonuclease I/metabolismo , Eletrocardiografia , Desenvolvimento Fetal , Feto/metabolismo , Redes Reguladoras de Genes , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Esclerose Múltipla/genética , Fenótipo , Regiões Promotoras Genéticas , Fatores de Transcrição/química , Fatores de Transcrição/genética
17.
Genome Biol ; 12(5): R43, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21569360

RESUMO

BACKGROUND: The development of complex organisms is believed to involve progressive restrictions in cellular fate. Understanding the scope and features of chromatin dynamics during embryogenesis, and identifying regulatory elements important for directing developmental processes remain key goals of developmental biology. RESULTS: We used in vivo DNaseI sensitivity to map the locations of regulatory elements, and explore the changing chromatin landscape during the first 11 hours of Drosophila embryonic development. We identified thousands of conserved, developmentally dynamic, distal DNaseI hypersensitive sites associated with spatial and temporal expression patterning of linked genes and with large regions of chromatin plasticity. We observed a nearly uniform balance between developmentally up- and down-regulated DNaseI hypersensitive sites. Analysis of promoter chromatin architecture revealed a novel role for classical core promoter sequence elements in directing temporally regulated chromatin remodeling. Another unexpected feature of the chromatin landscape was the presence of localized accessibility over many protein-coding regions, subsets of which were developmentally regulated or associated with the transcription of genes with prominent maternal RNA contributions in the blastoderm. CONCLUSIONS: Our results provide a global view of the rich and dynamic chromatin landscape of early animal development, as well as novel insights into the organization of developmentally regulated chromatin features.


Assuntos
Cromatina/genética , Desoxirribonuclease I/metabolismo , Biologia do Desenvolvimento , Drosophila melanogaster/genética , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Genoma de Inseto , Animais , Blastoderma/embriologia , Blastoderma/metabolismo , Padronização Corporal/genética , Cromatina/química , Imunoprecipitação da Cromatina , Desoxirribonuclease I/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Feminino , Loci Gênicos , Genômica , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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