Publications
138 results found
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.
Merkenschlager M, Amoils S, Roldan E, et al., 2004, Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice, Journal of Experimental Medicine, Vol: 200, Pages: 1437-1444, ISSN: 0022-1007
The differentiation of CD4 CD8 double positive (DP) thymocytes requires the irreversiblechoice between two alternative lineages, distinguished by the mutually exclusive expression ofeither CD4 or CD8. Differentiating DP cells transiently down-regulate both CD4 and CD8,and this has complicated the debate whether the mechanism of CD4/CD8 lineage choice is instructive, stochastic/selective, or more complex in nature. Using fluorescence in situ hybridization,we show that the stable silencing of coreceptor loci, and ultimately lineage choice, is predictedby the spatial repositioning of coreceptor alleles to centromeric heterochromatin domains.These data provide evidence that lineage-specific developmental programs are established earlyduring the transition from the DP to the single positive stage.
Hewitt SL, High FA, Reiner SL, et al., 2004, Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 34, Pages: 3604-3613, ISSN: 0014-2980
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- Citations: 97
Perry P, Sauer S, Billon N, et al., 2004, A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction, CELL CYCLE, Vol: 3, Pages: 1645-1650, ISSN: 1538-4101
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- Citations: 86
Takács K, Du Roure C, Nabarro S, et al., 2004, The regulated long-term delivery of therapeutic proteins by using antigen-specific B lymphocytes, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 101, Pages: 16298-16303, ISSN: 0027-8424
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- Citations: 11
Baxter J, Sauer S, Peters A, et al., 2004, Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes, EMBO JOURNAL, Vol: 23, Pages: 4462-4472, ISSN: 0261-4189
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- Citations: 91
Arney KL, Fisher AG, 2004, Epigenetic aspects of differentiation, JOURNAL OF CELL SCIENCE, Vol: 117, Pages: 4355-4363, ISSN: 0021-9533
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- Citations: 134
Su RC, Brown KE, Saaber S, et al., 2004, Dynamic assembly of silent chromatin during thymocyte maturation., Nat Genet, Vol: 36, Pages: 502-506, ISSN: 1061-4036
Considerable knowledge has been gained from temporal analyses of molecular events culminating in gene activation, but technical hurdles have hindered comparable studies of gene silencing. Here we describe the temporal assembly of silent chromatin at the mouse terminal transferase gene (Dntt), which is silenced and repositioned to pericentromeric heterochromatin during thymocyte maturation. Silencing was nucleated at the Dntt promoter by the ordered deacetylation of histone H3 at Lys9 (H3-Lys9), loss of methylation at H3-Lys4 and acquisition of methylation at H3-Lys9, followed by bidirectional spreading of each event. Deacetylation at H3-Lys9 coincided with pericentromeric repositioning, and neither of these early events required de novo protein synthesis. CpG methylation increased primarily in mature T cells that had left the thymus. A transformed thymocyte line supported reversible inactivation of Dntt without repositioning. In these cells, histone modification changes were nucleated at the promoter but did not spread. These results provide a foundation for elucidating the mechanisms of silent chromatin assembly during development.
Azuara V, Brown KE, Williams RRE, et al., 2003, Heritable gene silencing in lymphocytes delays chromatid resolution without affecting the timing of DNA replication, NATURE CELL BIOLOGY, Vol: 5, Pages: 668-U49, ISSN: 1465-7392
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- Citations: 86
Williams RRE, Fisher AG, 2003, Chromosomes, positions please!, NATURE CELL BIOLOGY, Vol: 5, Pages: 388-390, ISSN: 1465-7392
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- Citations: 20
Azuara V, Fisher AG, 2003, Maintaining Transcriptional States Through DNA Replication, CELL CYCLE, Vol: 2, Pages: 521-524, ISSN: 1538-4101
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- Citations: 2
Fisher AG, 2002, Cellular identity and lineage choice, NATURE REVIEWS IMMUNOLOGY, Vol: 2, Pages: 977-982, ISSN: 1474-1733
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- Citations: 80
Graf D, Nethisinghe S, Palmer DB, et al., 2002, The developmentally regulated expression of twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development, Journal of Experimental Medicine, Vol: 196, Pages: 163-171, ISSN: 0022-1007
The evolutionarily conserved, secreted protein Twisted gastrulation (Tsg) modulates morphogenetic effects of decapentaplegic (dpp) and its orthologs, the bone morphogenetic proteins 2 and 4 (BMP2/4), in early Drosophila and vertebrate embryos. We have uncovered a role for Tsg at a much later stage of mammalian development, during T cell differentiation in the thymus. BMP4 is expressed by thymic stroma and inhibits the proliferation of CD4(-)CD8(-) double-negative (DN) thymocytes and their differentiation to the CD4(+)CD8(+) double-positive (DP) stage in vitro. Tsg is expressed by thymocytes and up-regulated after T cell receptor signaling at two developmental checkpoints, the transition from the DN to the DP and from the DP to the CD4(+) or CD8(+) single-positive stage. Tsg can synergize with the BMP inhibitor chordin to block the BMP4-mediated inhibition of thymocyte proliferation and differentiation. These data suggest that the developmentally regulated expression of Tsg may allow thymocytes to temporarily withdraw from inhibitory BMP signals.
Baxter J, Merkenschlager M, Fisher AG, 2002, Nuclear organisation and gene expression, CURRENT OPINION IN CELL BIOLOGY, Vol: 14, Pages: 372-376, ISSN: 0955-0674
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- Citations: 46
Kosak ST, Skok JA, Medina KL, et al., 2002, Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development, SCIENCE, Vol: 296, Pages: 158-162, ISSN: 0036-8075
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- Citations: 564
Fisher AG, Merkenschlager M, 2002, Gene silencing, cell fate and nuclear organisation, CURRENT OPINION IN GENETICS & DEVELOPMENT, Vol: 12, Pages: 193-197, ISSN: 0959-437X
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- Citations: 76
Smale ST, Fisher AG, 2002, Chromatin structure and gene regulation in the immune system, ANNUAL REVIEW OF IMMUNOLOGY, Vol: 20, Pages: 427-462, ISSN: 0732-0582
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- Citations: 134
Smith K, Seddon B, Purbhoo MA, et al., 2001, Sensory adaptation in naive peripheral CD4 T cells, Journal of Experimental Medicine, Vol: 194, Pages: 1253-1261, ISSN: 1540-9538
T cell receptor interactions with peptide/major histocompatibility complex (pMHC) ligandscontrol the selection of T cells in the thymus as well as their homeostasis in peripheral lymphoidorgans. Here we show that pMHC contact modulates the expression of CD5 by naiveCD4 T cells in a process that requires the continued expression of p56lck. Reduced CD5 levelsin T cells deprived of pMHC contact are predictive of elevated Ca2 responses to subsequentTCR engagement by anti-CD3 or nominal antigen. Adaptation to peripheral pMHC contactmay be important for regulating naive CD4 T cell responsiveness.
Skok JA, Brown KE, Azuara V, et al., 2001, Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes, NATURE IMMUNOLOGY, Vol: 2, Pages: 848-854, ISSN: 1529-2908
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- Citations: 168
Graf D, Timmons PM, Hitchins M, et al., 2001, Evolutionary conservation, developmental expression, and genomic mapping of mammalian, Mammalian Genome, Vol: 012, Pages: 0554-0560, ISSN: 0938-8990
Graf D, Timmons PM, Hitchins M, et al., 2001, Evolutionary conservation, developmental expression, and genomic mapping of mammalian <i>Twisted gastrulation</i>, MAMMALIAN GENOME, Vol: 12, Pages: 554-560, ISSN: 0938-8990
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- Citations: 26
Brown KE, Amoils S, Horn JM, et al., 2001, Expression of α- and β-globin genes occurs within different nuclear domains in haemopoietic cells, NATURE CELL BIOLOGY, Vol: 3, Pages: 602-606, ISSN: 1465-7392
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- Citations: 132
Cobb BS, Morales-Alcelay S, Kleiger G, et al., 2000, Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding, GENES & DEVELOPMENT, Vol: 14, Pages: 2146-2160, ISSN: 0890-9369
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- Citations: 210
Lovatt M, Yang TH, Stauss HJ, et al., 2000, Different doses of agonistic ligand drive the maturation of functional CD4 and CD8 T cells from immature precursors, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 30, Pages: 371-381, ISSN: 0014-2980
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- Citations: 12
Brown KE, Baxter J, Graf D, et al., 1999, Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division, MOLECULAR CELL, Vol: 3, Pages: 207-217, ISSN: 1097-2765
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- Citations: 351
Ernst P, Hahm K, Cobb BS, et al., 1999, Mechanisms of transcriptional regulation in lymphocyte progenitors: Insight from an analysis of the terminal transferase promoter, COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY, Vol: 64, Pages: 87-97, ISSN: 0091-7451
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- Citations: 7
Hahm K, Cobb BS, McCarty AS, et al., 1998, Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin, GENES & DEVELOPMENT, Vol: 12, Pages: 782-796, ISSN: 0890-9369
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- Citations: 212
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