Publications
138 results found
Landeira D, Sauer S, Poot R, et al., 2010, Jarid2 is a PRC2 component in embryonic stem cells required for multi-lineage differentiation and recruitment of PRC1 and RNA Polymerase II to developmental regulators, NATURE CELL BIOLOGY, Vol: 12, Pages: 618-U214, ISSN: 1465-7392
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- Citations: 236
Pereira CF, Piccolo FM, Tsubouchi T, et al., 2010, ESCs Require PRC2 to Direct the Successful Reprogramming of Differentiated Cells toward Pluripotency, Cell stem cell, Vol: 6, Pages: 547-556
Stem Cell, 6 (2010) 547-556. doi:10.1016/j.stem.2010.04.013
Santos J, Pereira CF, Di-Gregorio A, et al., 2010, Differences in the epigenetic and reprogramming properties of pluripotent and extra-embryonic stem cells implicate chromatin remodelling as an important early event in the developing mouse embryo, Epigenetics & Chromatin, Vol: 3, ISSN: 1756-8935
BackgroundDuring early mouse development, two extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE) and the primitive endoderm (PrE). Epigenetic changes known to take place during these early stages include changes in DNA methylation and modified histones, as well as dynamic changes in gene expression.ResultsIn order to understand the role and extent of chromatin-based changes for lineage commitment within the embryo, we examined the epigenetic profiles of mouse embryonic stem (ES), trophectoderm stem (TS) and extra-embryonic endoderm (XEN) stem cell lines that were derived from the inner cell mass (ICM), TE and PrE, respectively. As an initial indicator of the chromatin state, we assessed the replication timing of a cohort of genes in each cell type, based on data that expressed genes and acetylated chromatin domains, generally, replicate early in S-phase, whereas some silent genes, hypoacetylated or condensed chromatin tend to replicate later. We found that many lineage-specific genes replicate early in ES, TS and XEN cells, which was consistent with a broadly 'accessible' chromatin that was reported previously for multiple ES cell lines. Close inspection of these profiles revealed differences between ES, TS and XEN cells that were consistent with their differing lineage affiliations and developmental potential. A comparative analysis of modified histones at the promoters of individual genes showed that in TS and ES cells many lineage-specific regulator genes are co-marked with modifications associated with active (H4ac, H3K4me2, H3K9ac) and repressive (H3K27me3) chromatin. However, in XEN cells several of these genes were marked solely by repressive modifications (such as H3K27me3, H4K20me3). Consistent with TS and XEN having a restricted developmental potential, we show that these cells selectively reprogramme somatic cells to induce the de novo expression of genes associated with extraembryonic differentiation.ConclusionsThese data p
Savarese F, Davila A, Nechanitzky R, et al., 2009, Satb1 and Satb2 regulate embryonic stem cell differentiation and <i>Nanog</i> expression, GENES & DEVELOPMENT, Vol: 23, Pages: 2625-2638, ISSN: 0890-9369
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- Citations: 111
Bruno L, Mazzarella L, Hoogenkamp M, et al., 2009, Runx proteins regulate Foxp3 expression, Journal of Experimental Medicine, Vol: 206, Pages: 2329-2337, ISSN: 0022-1007
Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of Foxp3 during inducible T reg cell differentiation, whereas the isolated dominant-negative Runt DNA binding domain antagonized de novo Foxp3 expression. Foxp3 expression in natural T reg cells remained dependent on Runx proteins and correlated with the binding of Runx/core-binding factor β to regulatory elements within the Foxp3 locus. Our data show that Runx and Foxp3 are components of a feed-forward loop in which Runx proteins contribute to the expression of Foxp3 and cooperate with Foxp3 proteins to regulate the expression of downstream target genes.
Hadjur S, Williams LM, Ryan NK, et al., 2009, Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus, Nature, Vol: 460, Pages: 410-U130, ISSN: 0028-0836
Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair1,2. In addition, evidence from model organisms3,4,5,6 and from human genetics7 suggests that cohesin is involved in the control of gene expression8,9. This non-canonical role has recently been rationalized by the findings that mammalian cohesin complexes are recruited to a subset of DNase I hypersensitive sites and to conserved noncoding sequences by the DNA-binding protein CTCF10,11,12,13. CTCF functions at insulators (which control interactions between enhancers and promoters) and at boundary elements (which demarcate regions of distinct chromatin structure)14, and cohesin contributes to its enhancer-blocking activity10,11. The underlying mechanisms remain unknown, and the full spectrum of cohesin functions remains to be determined. Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG. Hence, the ability of cohesin to constrain chromosome topology is used not only for the purpose of sister chromatid cohesion1,2, but also to dynamically define the spatial conformation of specific loci. This new aspect of cohesin function is probably important for normal development3,4,5,6 and disease7.
Hoogenkamp M, Lichtinger M, Krysinska H, et al., 2009, Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program, BLOOD, Vol: 114, Pages: 299-309, ISSN: 0006-4971
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- Citations: 91
Pereira CF, Fisher AG, 2009, Heterokaryon-based reprogramming for pluripotency., Curr Protoc Stem Cell Biol, Vol: Chapter 4, Pages: Unit-4B.1
Embryonic stem (ES) cells have the ability to self-renew, execute multiple lineage paths, and dominantly reprogram differentiated cells upon cell fusion. Here, we describe an approach that reprograms human B lymphocytes toward pluripotency by generating inter-species heterokaryons with mouse ES cells. This induces a human ES-specific gene expression profile, in which the extent and the rapidity of conversion allows us to compare the capacity of different mouse ES cell lines to dominantly induce pluripotency. This approach, coupled with pharmacological inhibition, gene knock-out, or knock-down permits factors that are required to directly induce reprogramming to be defined individually, as well as in combination. Experimental heterokaryons provide a simple and tractable approach to address the mechanisms underlying direct reprogramming to pluripotency. The procedure requires 5 days to complete.
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, Fisher AG, 2009, LOCKing in Cellular Potential, CELL STEM CELL, Vol: 4, Pages: 192-194, ISSN: 1934-5909
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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
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.
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
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
Stock JK, Giadrossi S, Casanova M, et 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
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- Citations: 484
Takousis P, Johonnett P, Williamson J, et 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
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- Citations: 5
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
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- Citations: 85
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.
Lande-Diner L, Zhang J, Ben-Porath I, et al., 2007, Role of DNA methylation in stable gene repression, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 282, Pages: 12194-12200, ISSN: 0021-9258
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- Citations: 116
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
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- Citations: 20
Spivakov M, Fisher AG, 2007, Epigenetic signatures of stem-cell identity, NATURE REVIEWS GENETICS, Vol: 8, Pages: 263-271, ISSN: 1471-0056
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- Citations: 295
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.
Roessler S, Gyoery I, Imhof S, et al., 2007, Distinct promoters mediate the regulation of <i>Ebf1</i> gene expression by interleukin-7 and Pax5, MOLECULAR AND CELLULAR BIOLOGY, Vol: 27, Pages: 579-594, ISSN: 0270-7306
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- Citations: 136
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.
Jorgensen HF, Giadrossi S, Casanova M, et 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
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- Citations: 58
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
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