Imperial College London

Professor Dame Amanda Fisher

Faculty of MedicineInstitute of Clinical Sciences

Head of the Institute of Clinical Sciences
 
 
 
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Contact

 

amanda.fisher

 
 
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Assistant

 

Ms Alessandra Lisini +44 (0)20 3313 8236

 
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Location

 

CRB (Clinical Research Building)Hammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

124 results found

Pereira CF, Terranova R, Ryan NK, Santos J, Morris KJ, Cui W, Merkenschlager M, Fisher AGet 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.

Journal article

Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O'Connor E, Shokat KM, Fisher AG, Merkenschlager Met 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

Journal article

Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschiager Met al., 2008, Cohesins functionally associate with CTCF on mammalian chromosome arms, CELL, Vol: 132, Pages: 422-433, ISSN: 0092-8674

Journal article

Stock JK, Giadrossi S, Casanova M, Brookes E, Vidal M, Koseki H, Brockdorff N, Fisher AG, Pombo Aet al., 2007, Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells, NATURE CELL BIOLOGY, Vol: 9, Pages: 1428-U174, ISSN: 1465-7392

Journal article

Takousis P, Johonnett P, Williamson J, Sasieni P, Warnes G, Forshew T, Azuara V, Fisher A, Wu P-J, Jones T, Vatcheva R, Beck S, Sheer Det al., 2007, Replication timing profile reflects the distinct functional and genomic features of the MHC class II region, CELL CYCLE, Vol: 6, Pages: 2393-2398, ISSN: 1538-4101

Journal article

Frye M, Fisher AG, Watt FM, 2007, Epidermal Stem Cells Are Defined by Global Histone Modifications that Are Altered by Myc-Induced Differentiation, PLOS ONE, Vol: 2, ISSN: 1932-6203

Journal article

Jorgensen HF, Azuara V, Amoils S, Spivakov M, Terry A, Nesterova T, Cobb BS, Ramsahoye B, Merkenschlager M, Fisher AGet 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.

Journal article

Lande-Diner L, Zhang J, Ben-Porath I, Amariglio N, Keshet I, Hecht M, Azuara V, Fisher AG, Rechavi G, Cedar Het al., 2007, Role of DNA methylation in stable gene repression, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 282, Pages: 12194-12200

Journal article

Giadrossi S, Dvorkina M, Fisher AG, 2007, Chromatin organization and differentiation in embryonic stem cell models, CURRENT OPINION IN GENETICS & DEVELOPMENT, Vol: 17, Pages: 132-138, ISSN: 0959-437X

Journal article

Spivakov M, Fisher AG, 2007, Epigenetic signatures of stem-cell identity, NATURE REVIEWS GENETICS, Vol: 8, Pages: 263-271, ISSN: 1471-0056

Journal article

Thompson EC, Cobb BS, Sabbattini P, Meixlsperger S, Parelho V, Liberg D, Taylor B, Dillon N, Georgopoulos K, Jumaa H, Smale ST, Fisher AG, Merkenschlager Met 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.

Journal article

Roessler S, Gyoery I, Imhof S, Spivakov M, Williams RR, Busslinger M, Fisher AG, Grosschedl Ret al., 2007, Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5, MOLECULAR AND CELLULAR BIOLOGY, Vol: 27, Pages: 579-594, ISSN: 0270-7306

Journal article

Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, Cook T, Smale ST, Sakaguchi S, Livesey FJ, Fisher AG, Merkenschlager Met 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.

Journal article

Jorgensen HF, Giadrossi S, Casanova M, Endoh M, Koseki H, Brockdorff N, Fisher AGet al., 2006, Stem cells primed for action - Polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells, CELL CYCLE, Vol: 5, Pages: 1411-1414, ISSN: 1538-4101

Journal article

Terranova R, Pereira CF, Du Roure C, Merkenschlager M, Fisher AGet 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

Journal article

Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M, Fisher AGet al., 2006, Chromatin signatures of pluripotent cell lines, NATURE CELL BIOLOGY, Vol: 8, Pages: 532-U189, ISSN: 1465-7392

Journal article

Du Roure C, Takacs K, Maxwell PH, Roberts I, Dazzi F, Cannella L, Merkenschlager M, Fisher AGet 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

Journal article

Williams RRE, Azuara V, Perry P, Sauer S, Dvorkina M, Jorgensen H, Roix J, McQueen P, Misteli T, Merkenschlager M, Fisher AGet al., 2006, Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus, JOURNAL OF CELL SCIENCE, Vol: 119, Pages: 132-140, ISSN: 0021-9533

Journal article

Terranova R, Sauer S, Merkenschlager M, Fisher AGet al., 2005, The reorganisation of constitutive heterochromatin in differentiating muscle requires HDAC activity, EXPERIMENTAL CELL RESEARCH, Vol: 310, Pages: 344-356, ISSN: 0014-4827

Journal article

Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, Godwin J, Wilson CB, Brockdorff N, Fisher AG, Smale ST, Merkenschlager Met 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.

Journal article

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

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

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

Takacs K, Du Roure C, Nabarro S, Dillon N, McVey JH, Webster Z, MacNeil A, Bartok 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

Arney KL, Fisher AG, 2004, Epigenetic aspects of differentiation, JOURNAL OF CELL SCIENCE, Vol: 117, Pages: 4355-4363, ISSN: 0021-9533

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

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

Williams RRE, Fisher AG, 2003, Chromosomes, positions please!, NATURE CELL BIOLOGY, Vol: 5, Pages: 388-390, ISSN: 1465-7392

Journal article

Azuara V, Fisher AG, 2003, Maintaining Transcriptional States Through DNA Replication, CELL CYCLE, Vol: 2, Pages: 521-524, ISSN: 1538-4101

Journal article

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