Publications
162 results found
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.
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
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
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
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.
Liberg D, Smale ST, Merkenschlager M, 2003, Upstream of ikaros, TRENDS IN IMMUNOLOGY, Vol: 24, Pages: 567-570, ISSN: 1471-4906
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- Citations: 16
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
Yang TH, Lovatt M, Merkenschlager M, et al., 2002, Comparison of the frequency of peptide-specific cytotoxic T lymphocytes restricted by self- and allo-MHC following <i>in vitro</i> T cell priming, INTERNATIONAL IMMUNOLOGY, Vol: 14, Pages: 1283-1290, ISSN: 0953-8178
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- Citations: 1
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
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
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.
Davodeau F, Difilippantonio M, Roldan E, et al., 2001, The tight interallelic positional coincidence that distinguishes T-cell receptor Jα usage does not result from homologous chromosomal pairing during VαJα rearrangement, EMBO JOURNAL, Vol: 20, Pages: 4717-4729, ISSN: 0261-4189
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- Citations: 37
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
Trinh LA, Ferrini R, Cobb BS, et al., 2001, Down-regulation of TDT transcription in CD4<SUP>+</SUP>CD8<SUP>+</SUP> thymocytes by Ikaros proteins in direct competition with an Ets activator, GENES & DEVELOPMENT, Vol: 15, Pages: 1817-1832, ISSN: 0890-9369
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- Citations: 120
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
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
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
Barcenas-Morales G, Merkenschlager M, Wahid F, et al., 2000, Recessive expression of the H2A-controlled immune response phenotype depends critically on antigen dose, IMMUNOLOGY, Vol: 99, Pages: 221-228, ISSN: 0019-2805
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- Citations: 3
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
Brown KE, Guest SS, Smale ST, et al., 1997, Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin, CELL, Vol: 91, Pages: 845-854, ISSN: 0092-8674
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- Citations: 648
Merkenschlager M, Graf D, Lovatt M, et al., 1997, How many thymocytes audition for selection?, Journal of Experimental Medicine, Vol: 186, Pages: 1149-1158, ISSN: 0022-1007
T cell maturation requires the rearrangement of clonotypic T cell receptors (TCR) capable of interacting with major histocompatibility complex (MHC) ligands to initiate positive and negative selection. Only 3–5% of thymocytes mature to join the peripheral T cell pool. To investigate the basis for this low success rate, we have measured the frequency of preselection thymocytes capable of responding to MHC. As many as one in five MHC-naive thymocytes show upregulation of activation markers on exposure to MHC-expressing thymic stroma in short-term reaggregate culture. The majority of these cells display physiological changes consistent with entry into the selection process within 24 h. By exposing TCR transgenic thymocytes to a range of MHC–peptide complexes, we show that CD69 induction is indicative of thymocyte selection, positive or negative. Our data provide evidence that the fraction of thymocytes that qualify to enter the thymic selection process far exceeds the fraction that successfully complete it, and suggest that most MHC-reactive thymocytes are actively eliminated in the course of selection.
Graf D, Fisher AG, Merkenschlager M, 1997, Rational primer design greatly improves differential display PCR (DD-PCR), NUCLEIC ACIDS RESEARCH, Vol: 25, Pages: 2239-2240, ISSN: 0305-1048
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- Citations: 29
Merkenschlager M, 1996, Tracing interactions of thymocytes with individual stromal cell partners, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 26, Pages: 892-896, ISSN: 0014-2980
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- Citations: 29
FISHER AG, BURDET C, BUNCE C, et al., 1995, LYMPHOPROLIFERATIVE DISORDERS IN IL-7 TRANSGENIC MICE - EXPANSION OF IMMATURE B-CELLS WHICH RETAIN MACROPHAGE POTENTIAL, INTERNATIONAL IMMUNOLOGY, Vol: 7, Pages: 415-423, ISSN: 0953-8178
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- Citations: 62
FISHER A, CEREDIG R, MERKENSCHLAGER M, 1994, LINEAGE POTENTIAL OF LYMPHOID PRECURSOR CELLS FROM NORMAL AND IL-7 TRANSGENIC MICE, JOURNAL OF CELLULAR BIOCHEMISTRY, Pages: 420-420, ISSN: 0730-2312
MERKENSCHLAGER M, FISHER AG, 1992, SELECTIVE MANIPULATION OF THE HUMAN T-CELL RECEPTOR REPERTOIRE EXPRESSED BY THYMOCYTES IN ORGAN-CULTURE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 89, Pages: 4255-4259, ISSN: 0027-8424
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- Citations: 13
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