共查询到20条相似文献,搜索用时 31 毫秒
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Dickins RA Hemann MT Zilfou JT Simpson DR Ibarra I Hannon GJ Lowe SW 《Nature genetics》2005,37(11):1289-1295
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Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation 总被引:7,自引:0,他引:7
Stegmaier K Ross KN Colavito SA O'Malley S Stockwell BR Golub TR 《Nature genetics》2004,36(3):257-263
Chemical genomics involves generating large collections of small molecules and using them to modulate cellular states. Despite recent progress in the systematic synthesis of structurally diverse compounds, their use in screens of cellular circuitry is still an ad hoc process. Here, we outline a general, efficient approach called gene expression-based high-throughput screening (GE-HTS) in which a gene expression signature is used as a surrogate for cellular states, and we describe its application in a particular setting: the identification of compounds that induce the differentiation of acute myeloid leukemia cells. In screening 1,739 compounds, we identified 8 that reliably induced the differentiation signature and, furthermore, yielded functional evidence of bona fide differentiation. The results indicate that GE-HTS may be a powerful, general approach for chemical screening. 相似文献
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Huang E Ishida S Pittman J Dressman H Bild A Kloos M D'Amico M Pestell RG West M Nevins JR 《Nature genetics》2003,34(2):226-230
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Strategies for dissecting epigenetic mechanisms in the mouse 总被引:4,自引:0,他引:4
Epigenetics generally refers to heritable changes in gene expression that are independent of nucleotide sequence. With complete genome sequences in hand, understanding the epigenetic control of genomes is the next step towards comprehending how the same DNA sequence gives rise to different cells, lineages and organs. Epigenetics also contributes to individual variation in normal biology and in disease states. The mouse provides a unique opportunity to understand how epigenetic differences contribute to both development and disease in a tractable mammalian system. Here we discuss current approaches and protocols used to study epigenetics in the mouse, including loss-of-function studies, mutagenesis screens, somatic cell nuclear transfer, genomics and proteomics. 相似文献
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A lentivirus-based system to functionally silence genes in primary mammalian cells,stem cells and transgenic mice by RNA interference 总被引:87,自引:0,他引:87
Rubinson DA Dillon CP Kwiatkowski AV Sievers C Yang L Kopinja J Rooney DL Zhang M Ihrig MM McManus MT Gertler FB Scott ML Van Parijs L 《Nature genetics》2003,33(3):401-406
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Cleary MA van Raamsdonk CD Levorse J Zheng B Bradley A Tilghman SM 《Nature genetics》2001,29(1):78-82
Genomic imprinting is an epigenetic process in which the activity of a gene is determined by its parent of origin. Mechanisms governing genomic imprinting are just beginning to be understood. However, the tendency of imprinted genes to exist in chromosomal clusters suggests a sharing of regulatory elements. To better understand imprinted gene clustering, we disrupted a cluster of imprinted genes on mouse distal chromosome 7 using the Cre/loxP recombination system. In mice carrying a site-specific translocation separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1, Ascl2, H19 and Igf2, is unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l and Tssc3 on chromosome 11 are affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. These data support the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C expression. These results underscore the importance of gene clustering for the proper regulation of imprinted genes. 相似文献
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Population genomics of human gene expression 总被引:1,自引:0,他引:1
Stranger BE Nica AC Forrest MS Dimas A Bird CP Beazley C Ingle CE Dunning M Flicek P Koller D Montgomery S Tavaré S Deloukas P Dermitzakis ET 《Nature genetics》2007,39(10):1217-1224
Genetic variation influences gene expression, and this variation in gene expression can be efficiently mapped to specific genomic regions and variants. Here we have used gene expression profiling of Epstein-Barr virus-transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find that gene expression is heritable and that differentiation between populations is in agreement with earlier small-scale studies. A detailed association analysis of over 2.2 million common SNPs per population (5% frequency in HapMap) with gene expression identified at least 1,348 genes with association signals in cis and at least 180 in trans. Replication in at least one independent population was achieved for 37% of cis signals and 15% of trans signals, respectively. Our results strongly support an abundance of cis-regulatory variation in the human genome. Detection of trans effects is limited but suggests that regulatory variation may be the key primary effect contributing to phenotypic variation in humans. We also explore several methodologies that improve the current state of analysis of gene expression variation. 相似文献
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A genome-wide survey of RAS transformation targets 总被引:28,自引:0,他引:28
Zuber J Tchernitsa OI Hinzmann B Schmitz AC Grips M Hellriegel M Sers C Rosenthal A Schäfer R 《Nature genetics》2000,24(2):144-152
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Jacobsen M Schweer D Ziegler A Gaber R Schock S Schwinzer R Wonigeit K Lindert RB Kantarci O Schaefer-Klein J Schipper HI Oertel WH Heidenreich F Weinshenker BG Sommer N Hemmer B 《Nature genetics》2000,26(4):495-499
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families. 相似文献
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Germline epimutation of MLH1 in individuals with multiple cancers 总被引:12,自引:0,他引:12
Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. We hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. Here we report two individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lack evidence of genetic mutation in any mismatch repair gene but have had multiple primary tumors that show mismatch repair deficiency, and both meet clinical criteria for hereditary nonpolyposis colorectal cancer. The epimutation was also present in spermatozoa of one of the individuals, indicating a germline defect and the potential for transmission to offspring. Germline epimutation provides a mechanism for phenocopying of genetic disease. The mosaicism and nonmendelian inheritance that are characteristic of epigenetic states could produce patterns of disease risk that resemble those of polygenic or complex traits. 相似文献
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Heritable and inducible genetic interference by double-stranded RNA encoded by transgenes 总被引:56,自引:0,他引:56
Double-stranded RNA interference (RNAi) is an effective method for disrupting expression of specific genes in Caenorhabditis elegans and other organisms. Applications of this reverse-genetics tool, however, are somewhat restricted in nematodes because introduced dsRNA is not stably inherited. Another difficulty is that RNAi disruption of late-acting genes has been generally less consistent than that of embryonically expressed genes, perhaps because the concentration of dsRNA becomes lower as cellular division proceeds or as developmental time advances. In particular, some neuronally expressed genes appear refractory to dsRNA-mediated interference. We sought to extend the applicability of RNAi by in vivo expression of heritable inverted-repeat (IR) genes. We assayed the efficacy of in vivo-driven RNAi in three situations for which heritable, inducible RNAi would be advantageous: (i) production of large numbers of animals deficient for gene activities required for viability or reproduction; (ii) generation of large populations of phenocopy mutants for biochemical analysis; and (iii) effective gene inactivation in the nervous system. We report that heritable IR genes confer potent and specific gene inactivation for each of these applications. We suggest that a similar strategy might be used to test for dsRNA interference effects in higher organisms in which it is feasible to construct transgenic animals, but impossible to directly or transiently introduce high concentrations of dsRNA. 相似文献
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Growth factor signaling leads to the induction or repression of immediate early genes, but how these genes act collectively as effectors of downstream processes remains unresolved. We have used gene trap-coupled microarray analysis to identify and mutate multiple platelet-derived growth factor (PDGF) intermediate early genes in mice. Mutations in these genes lead to a high frequency of phenotypes that affect the same cell types and processes as those controlled by the PDGF pathway. We conclude that these genes form a network that controls specific processes downstream of PDGF signaling. 相似文献
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Hansen KD Timp W Bravo HC Sabunciyan S Langmead B McDonald OG Wen B Wu H Liu Y Diep D Briem E Zhang K Irizarry RA Feinberg AP 《Nature genetics》2011,43(8):768-775
Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal tissue, in colon, lung, breast, thyroid and Wilms' tumors, with intermediate variation in adenomas. Whole-genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. We suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer that may contribute to tumor heterogeneity. 相似文献