Publications
162 results found
Raaijmakers MHGP, Mukherjee S, Guo S, et al., 2009, DELETION OF DICER1 FROM OSTEOPROGENITOR CELLS IS SUFFICIENT TO INDUCE MYELODYSPLASIA AND HEMATOPOIETIC NEOPLASIA, 14th Annual Meeting of the European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 227-227, ISSN: 0390-6078
Bowers SR, Mirabella F, Calero-Nieto FJ, et al., 2009, A Conserved Insulator That Recruits CTCF and Cohesin Exists between the Closely Related but Divergently Regulated Interleukin-3 and Granulocyte-Macrophage Colony-Stimulating Factor Genes, MOLECULAR AND CELLULAR BIOLOGY, Vol: 29, Pages: 1682-1693, ISSN: 0270-7306
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- Citations: 22
Caparros M-L, Fisher AG, Merkenschlager M, 2009, Chromosomes and expression mechanisms: life on the edge, CURRENT OPINION IN GENETICS & DEVELOPMENT, Vol: 19, Pages: 97-98, ISSN: 0959-437X
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- Citations: 1
Jorgensen HF, Terry A, Beretta C, et al., 2009, REST selectively represses a subset of RE1-containing neuronal genes in mouse embryonic stem cells, DEVELOPMENT, Vol: 136, Pages: 715-721, ISSN: 0950-1991
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- Citations: 65
Jorgensen HF, Chen Z-F, Merkenschlager M, et al., 2009, Is REST required for ESC pluripotency?, NATURE, Vol: 457, Pages: E4-E5, ISSN: 0028-0836
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- Citations: 48
Hadjur S, Bruno L, Hertweck A, et al., 2009, IL4 blockade of inducible regulatory T cell differentiation: The role of Th2 cells, Gata3 and PU.1, IMMUNOLOGY LETTERS, Vol: 122, Pages: 37-43, ISSN: 0165-2478
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- Citations: 23
Taylor B, Cobb BS, Bruno L, et al., 2009, A reappraisal of evidence for probabilistic models of allelic exclusion, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 516-521, ISSN: 0027-8424
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- Citations: 9
Shi S, Yu L, Chiu C, et al., 2008, Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 19, Pages: 2159-2169, ISSN: 1046-6673
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- Citations: 292
Nesterova TB, Popova BC, Cobb BS, et al., 2008, Dicer regulates Xist promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a, Epigenetics & Chromatin, Vol: 1, ISSN: 1756-8935
BackgroundX chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males. Chromosome silencing is triggered in cis by expression of the non-coding RNA Xist. As such, correct regulation of the Xist gene promoter is required to establish appropriate X chromosome activity both in males and females. Studies to date have demonstrated co-transcription of an antisense RNA Tsix and low-level sense transcription prior to onset of X inactivation. The balance of sense and antisense RNA is important in determining the probability that a given Xist allele will be expressed, termed the X inactivation choice, when X inactivation commences.ResultsHere we investigate further the mechanism of Xist promoter regulation. We demonstrate that both sense and antisense transcription modulate Xist promoter DNA methylation in undifferentiated embryonic stem (ES) cells, suggesting a possible mechanistic basis for influencing X chromosome choice. Given the involvement of sense and antisense RNAs in promoter methylation, we investigate a possible role for the RNA interference (RNAi) pathway. We show that the Xist promoter is hypomethylated in ES cells deficient for the essential RNAi enzyme Dicer, but that this effect is probably a secondary consequence of reduced levels of de novo DNA methyltransferases in these cells. Consistent with this we find that Dicer-deficient XY and XX embryos show appropriate Xist expression patterns, indicating that Xist gene regulation has not been perturbed.ConclusionWe conclude that Xist promoter methylation prior to the onset of random X chromosome inactivation is influenced by relative levels of sense and antisense transcription but that this probably occurs independent of the RNAi pathway. We discuss the implications for this data in terms of understanding Xist gene regulation and X chromosome choice in random X chromosome inactivation.
Gartenberg MR, Merkenschlager M, 2008, Condensin goes with the family but not with the flow, Genome Biology, Vol: 9, ISSN: 1474-7596
Condensin and cohesin are loaded onto yeast chromosomes by a common mechanism at RNA polymerase III transcribed genes. Whereas cohesin translocates from these loading sites to mediate cohesion at secondary locations, condensin remains, bringing distant sites together into clusters.Structural maintenance of chromosome proteins, or SMCs for short, are components of a variety of complexes that are central to the organization, utilization and segregation of chromosomes [1]. SMCs are unusually large proteins that fold on themselves to form long coiled coils with an ATPase head at one end. A dimerization motif at the other end allows the proteins to form SMC pairs, which in turn associate with additional structural and regulatory factors. The Smc1 and Smc3 dimer forms the core of the complex known as cohesin, which mediates sister-chromatid cohesion by directly binding sister chromatids together until the onset of anaphase. The Smc2 and Smc4 dimer forms the core of condensin, a protein complex that facilitates DNA chromosome condensation in preparation for mitotic segregation. An additional pair of proteins, Smc5 and Smc6, forms the core of a less well understood complex with important roles in several critical processes including DNA damage checkpoint response and repair. Figure 1a shows schematic representations of SMC complexes and their subunits.
Suarez Y, Fernandez-Hernando C, Yu J, et al., 2008, Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 105, Pages: 14082-14087, ISSN: 0027-8424
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- Citations: 394
Pereira CF, Terranova R, Ryan NK, et al., 2008, Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2, PLoS Genetics, Vol: 4, ISSN: 1553-7390
Differentiated cells can be reprogrammed through the formation of heterokaryons and hybrid cells when fused withembryonic stem (ES) cells. Here, we provide evidence that conversion of human B-lymphocytes towards a multipotent stateis initiated much more rapidly than previously thought, occurring in transient heterokaryons before nuclear fusion and celldivision. Interestingly, reprogramming of human lymphocytes by mouse ES cells elicits the expression of a human ESspecific gene profile, in which markers of human ES cells are expressed (hSSEA4, hFGF receptors and ligands), but markersthat are specific to mouse ES cells are not (e.g., Bmp4 and LIF receptor). Using genetically engineered mouse ES cells, wedemonstrate that successful reprogramming of human lymphocytes is independent of Sox2, a factor thought to be requiredfor induced pluripotent stem (iPS) cells. In contrast, there is a distinct requirement for Oct4 in the establishment but not themaintenance of the reprogrammed state. Experimental heterokaryons, therefore, offer a powerful approach to trace thecontribution of individual factors to the reprogramming of human somatic cells towards a multipotent state.
Bruno L, Merkenschlager M, 2008, Directing T cell differentiation and function with small molecule inhibitors, CELL CYCLE, Vol: 7, Pages: 2296-2298, ISSN: 1538-4101
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- Citations: 12
Sauer S, Bruno L, Hertweck A, et al., 2008, T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 105, Pages: 7797-7802, ISSN: 0027-8424
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- Citations: 674
Rowel E, Merkenschlager M, Wilson CB, 2008, Long-range regulation of cytokine gene expression, CURRENT OPINION IN IMMUNOLOGY, Vol: 20, Pages: 272-280, ISSN: 0952-7915
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- Citations: 20
Merkenschlager M, Wilson CB, 2008, RNAi and chromatin in T cell development and function, CURRENT OPINION IN IMMUNOLOGY, Vol: 20, Pages: 131-138, ISSN: 0952-7915
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- Citations: 14
Koralov SB, Muljo SA, Galler GR, et al., 2008, Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage, CELL, Vol: 132, Pages: 860-874, ISSN: 0092-8674
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- Citations: 463
Kobayashi T, Lu J, Cobb BS, et al., 2008, Dicer-dependent pathways regulate chondrocyte proliferation and differentiation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 105, Pages: 1949-1954, ISSN: 0027-8424
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- Citations: 290
Parelho V, Hadjur S, Spivakov M, et al., 2008, Cohesins functionally associate with CTCF on mammalian chromosome arms, CELL, Vol: 132, Pages: 422-433, ISSN: 0092-8674
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- Citations: 679
Jorgensen HF, Azuara V, Amoils S, et al., 2007, The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells, Genome Biology, Vol: 8, ISSN: 1474-7596
BackgroundThe time of locus replication during S-phase is tightly regulated and correlates with chromatin state. Embryonic stem (ES) cells have an unusual chromatin profile where many developmental regulator genes that are not yet expressed are marked by both active and repressive histone modifications. This poised or bivalent state is also characterized by locus replication in early S-phase in ES cells, while replication timing is delayed in cells with restricted developmental options.ResultsHere we used a panel of mutant mouse ES cell lines lacking important chromatin modifiers to dissect the relationship between chromatin structure and replication timing. We show that temporal control of satellite DNA replication is sensitive to loss of a variety of chromatin modifiers, including Mll, Eed, Dnmt1, Suv39h1/h2 and Dicer. The replication times of many single copy loci, including a 5 Mb contiguous region surrounding the Rex1 gene, were retained in chromatin modifier mutant ES cells, although a subset of loci were affected.ConclusionThis analysis demonstrates the importance of chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells and highlights the sensitivity of some single copy loci to the influence of chromatin modifiers. Abundant histone acetylation is shown to correlate well with early replication. Surprisingly, loss of DNA methylation or histone methylation was tolerated by many loci, suggesting that these modifications may be less influential for the timing of euchromatin replication.
Thompson EC, Cobb BS, Sabbattini P, et al., 2007, Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits., Immunity, Vol: 26, Pages: 335-344, ISSN: 1074-7613
Ikaros DNA-binding proteins are critical for the development of lymphocytes and other hematopoietic lineages, but it remains unclear how they cooperate with other regulators of signaling and transcription to achieve ordered gene expression during development. Here, we show that Ikaros proteins regulate the pre-BCR component lambda5 in a stage-specific manner. In pre-BI cells, Ikaros modulated lambda5 expression in competition with the transcriptional activator EBF. This required Ikaros binding to the Igll1 (lambda5) promoter and was abolished either by mutation of the Ikaros DNA-binding domain or by deletion of a single Ikaros site from the Igll1 promoter. At the transition from the pre-BI to pre-BII stage, the expression of the Ikaros family member Aiolos was upregulated and required for the efficient silencing of Igll1. Aiolos expression was controlled by pre-BCR signals via the adaptor protein SLP-65. Thus, pre-BCR signaling regulates Aiolos and the silencing of Igll1 via a developmental-stage-specific feedback loop.
Cobb BS, Hertweck A, Smith J, et al., 2006, A role for Dicer in immune regulation, Journal of Experimental Medicine, Vol: 203, Pages: 2519-2527, ISSN: 0022-1007
Micro RNAs (miRNAs) regulate gene expression at the posttranscriptional level. Here we show that regulatory T (T reg) cells have a miRNA profile distinct from conventional CD4 T cells. A partial T reg cell-like miRNA profile is conferred by the enforced expression of Foxp3 and, surprisingly, by the activation of conventional CD4 T cells. Depleting miRNAs by eliminating Dicer, the RNAse III enzyme that generates functional miRNAs, reduces T reg cell numbers and results in immune pathology. Dicer facilitates, in a cell-autonomous fashion, the development of T reg cells in the thymus and the efficient induction of Foxp3 by transforming growth factor beta. These results suggest that T reg cell development involves Dicer-generated RNAs.
Terranova R, Pereira CF, Du Roure C, et al., 2006, Acquisition and extinction of gene expression programs are separable events in heterokaryon reprogramming, JOURNAL OF CELL SCIENCE, Vol: 119, Pages: 2065-2072, ISSN: 0021-9533
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- Citations: 49
Azuara V, Perry P, Sauer S, et al., 2006, Chromatin signatures of pluripotent cell lines, NATURE CELL BIOLOGY, Vol: 8, Pages: 532-U189, ISSN: 1465-7392
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- Citations: 1023
Wilson CB, Merkenschlager M, 2006, Chromatin structure and gene regulation in T cell development and function, CURRENT OPINION IN IMMUNOLOGY, Vol: 18, Pages: 143-151, ISSN: 0952-7915
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- Citations: 27
Du Roure C, Takács K, Maxwell PH, et al., 2006, Correction of severe anaemia using immuno-regulated gene therapy is achieved by restoring the early erythroblast compartment, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 132, Pages: 608-614, ISSN: 0007-1048
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- Citations: 2
Williams RRE, Azuara V, Perry P, et al., 2006, Neural induction promotes large-scale chromatin reorganisation of the <i>Mash1</i> locus, JOURNAL OF CELL SCIENCE, Vol: 119, Pages: 132-140, ISSN: 0021-9533
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- Citations: 234
Terranova R, Sauer S, Merkenschlager M, et al., 2005, The reorganisation of constitutive heterochromatin in differentiating muscle requires HDAC activity, EXPERIMENTAL CELL RESEARCH, Vol: 310, Pages: 344-356, ISSN: 0014-4827
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- Citations: 67
Cobb BS, Nesterova TB, Thompson E, et al., 2005, T cell lineage choice and differentiation in the absence of the RNase III enzyme dicer, Journal of Experimental Medicine, Vol: 201, Pages: 1367-1373, ISSN: 0022-1007
The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of alphabeta lineage cells, whereas the numbers of gammadelta-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs.
Fisher A, Merkenschlager M, 2005, Gene silencing in lymphocyte development, SEMINARS IN IMMUNOLOGY, Vol: 17, Pages: 103-103, ISSN: 1044-5323
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