Imperial College London

ProfessorMatthiasMerkenschlager

Faculty of MedicineInstitute of Clinical Sciences

Professor of Cell Biology
 
 
 
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Contact

 

+44 (0)20 3313 8239matthias.merkenschlager

 
 
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Location

 

5.11DLMS BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

162 results found

Merkenschlager M, Amoils S, Roldan E, Rahemtulla A, O'Connor E, Fisher AG, Brown KEet 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.

Journal article

Perry P, Sauer S, Billon N, Richardson WD, Spivakov M, Warnes G, Livesey FJ, Merkenschlager M, Fisher AG, Azuara Vet 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

Journal article

Hewitt SL, High FA, Reiner SL, Fisher AG, Merkenschlager Met 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

Journal article

Takács K, Du Roure C, Nabarro S, Dillon N, McVey JH, Webster Z, MacNeil A, Bartók L, Higgins C, Gray D, Merkenschlager M, Fisher AGet 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

Journal article

Baxter J, Sauer S, Peters A, John R, Williams R, Caparros ML, Arney K, Otte A, Jenuwein T, Merkenschlager M, Fisher AGet al., 2004, Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes, EMBO JOURNAL, Vol: 23, Pages: 4462-4472, ISSN: 0261-4189

Journal article

Su RC, Brown KE, Saaber S, Fisher AG, Merkenschlager M, Smale STet 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.

Journal article

Liberg D, Smale ST, Merkenschlager M, 2003, Upstream of ikaros, TRENDS IN IMMUNOLOGY, Vol: 24, Pages: 567-570, ISSN: 1471-4906

Journal article

Azuara V, Brown KE, Williams RRE, Webb N, Dillon N, Festenstein R, Buckle V, Merkenschlager M, Fisher AGet 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

Journal article

Yang TH, Lovatt M, Merkenschlager M, Stauss HJet 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

Journal article

Graf D, Nethisinghe S, Palmer DB, Fisher AG, Merkenschlager Met 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.

Journal article

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

Journal article

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

Journal article

Smith K, Seddon B, Purbhoo MA, Zamoyska R, Fisher AG, Merkenslchlager Met 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.

Journal article

Davodeau F, Difilippantonio M, Roldan E, Malissen M, Casanova JL, Couedel C, Morcet JF, Merkenschlager M, Nussenzweig A, Bonneville M, Malissen Bet 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

Journal article

Skok JA, Brown KE, Azuara V, Caparros ML, Baxter J, Takacs K, Dillon N, Gray D, Perry RP, Merkenschlager M, Fisher AGet al., 2001, Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes, NATURE IMMUNOLOGY, Vol: 2, Pages: 848-854, ISSN: 1529-2908

Journal article

Trinh LA, Ferrini R, Cobb BS, Weinmann AS, Hahm K, Ernst P, Garraway IP, Merkenschlager M, Smale STet 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

Journal article

Graf D, Timmons PM, Hitchins M, Episkopou V, Moore G, Ito T, Fujiyama A, Fisher AG, Merkenschlager Met 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

Journal article

Graf D, Timmons PM, Hitchins M, Episkopou V, Moore G, Ito T, Fujiyama A, Fisher AG, Merkenschlager Met al., 2001, Evolutionary conservation, developmental expression, and genomic mapping of mammalian, Mammalian Genome, Vol: 012, Pages: 0554-0560, ISSN: 0938-8990

Journal article

Brown KE, Amoils S, Horn JM, Buckle VJ, Higgs DR, Merkenschlager M, Fisher AGet 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

Journal article

Barcenas-Morales G, Merkenschlager M, Wahid F, Döffinger R, Ivanyi Jet 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

Journal article

Lovatt M, Yang TH, Stauss HJ, Fisher AG, Merkenschlager Met 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

Journal article

Brown KE, Baxter J, Graf D, Merkenschlager M, Fisher AGet 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

Journal article

Ernst P, Hahm K, Cobb BS, Brown KE, Trinh LA, McCarty AS, Merkenschlager M, Klug CA, Fisher AG, Smale STet 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

Journal article

Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M, Fisher AGet al., 1997, Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin, CELL, Vol: 91, Pages: 845-854, ISSN: 0092-8674

Journal article

Merkenschlager M, Graf D, Lovatt M, Bommhardt U, Zamoyska R, Fisher AGet 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.

Journal article

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

Journal article

Merkenschlager M, 1996, Tracing interactions of thymocytes with individual stromal cell partners, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 26, Pages: 892-896, ISSN: 0014-2980

Journal article

FISHER AG, BURDET C, BUNCE C, MERKENSCHLAGER M, CEREDIG Ret 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

Journal article

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

Journal article

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

Journal article

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