8 results on '"Lisa von Paleske"'
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2. Myc depletion induces a pluripotent dormant state mimicking diapause
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Áine M. Prendergast, Andreas Trumpp, Simon Haas, Frank Edenhofer, Daniel Baumgärtner, Nina Cabezas-Wallscheid, Alejandro Reyes, Lisa von Paleske, Ann Atzberger, Roberta Scognamiglio, Austin Smith, Marieke A.G. Essers, Thorsten Boroviak, Ulrich Kloz, Philipp Wörsdörfer, Paul Bertone, Marc Thier, Larissa S. Carnevalli, Wolfgang Huber, Franciscus van der Hoeven, Robert N. Eisenman, Sandro Altamura, Bertone, Paul [0000-0001-5059-4829], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,Cancer Research ,Genes, myc ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Gene Knockout Techniques ,Mice ,Transcription (biology) ,Protein biosynthesis ,Animals ,ddc:610 ,Embryonic Stem Cells ,reproductive and urinary physiology ,Cell Proliferation ,Cell growth ,Biochemistry, Genetics and Molecular Biology(all) ,Embryo ,Embryo, Mammalian ,Embryonic stem cell ,Molecular biology ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Blastocyst ,embryonic structures ,Dormancy ,Female ,Embryonic diapause ,Stem cell - Abstract
Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state., This work was supported by the FOR2033 and SFB873 funded by the Deutsche Forschungsgemeinschaft (DFG), the Dietmar Hopp Foundation (all to A.T.), and the Wellcome Trust (to A.S.).
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- 2018
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3. Hematopoietic stem cell quiescence and function are controlled by the CYLD–TRAF2–p38MAPK pathway
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Yilang Tang, Massimo Saini, Ari Waisman, Melania Tesio, Elizabeth Macintyre, Andreas Trumpp, Lisa von Paleske, Katja Müdder, and Manolis Pasparakis
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TRAF2 ,Tumor suppressor gene ,MAP Kinase Signaling System ,Immunology ,Regulator ,Biology ,p38 Mitogen-Activated Protein Kinases ,Article ,Mice ,medicine ,Animals ,Immunology and Allergy ,Mice, Knockout ,Regulation of gene expression ,NF-kappa B ,Hematopoietic stem cell ,Cell Biology ,Hematopoietic Stem Cells ,TNF Receptor-Associated Factor 2 ,Phenotype ,Deubiquitinating Enzyme CYLD ,Cell biology ,Cysteine Endopeptidases ,Haematopoiesis ,medicine.anatomical_structure ,Gene Expression Regulation ,Mutation ,Stem cell - Abstract
Tesio at al. identify a novel pathway controlled by the tumor suppressor and deubiquitinase cylindromatosis (CYLD), which is involved in the regulation of hematopoietic stem cell quiescence and repopulation potential., The status of long-term quiescence and dormancy guarantees the integrity of hematopoietic stem cells (HSCs) during adult homeostasis. However the molecular mechanisms regulating HSC dormancy remain poorly understood. Here we show that cylindromatosis (CYLD), a tumor suppressor gene and negative regulator of NF-κB signaling with deubiquitinase activity, is highly expressed in label-retaining dormant HSCs (dHSCs). Moreover, Cre-mediated conditional elimination of the catalytic domain of CYLD induced dHSCs to exit quiescence and abrogated their repopulation and self-renewal potential. This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor–associated factor 2). HSCs expressing a mutant CYLD with an intact catalytic domain, but unable to bind TRAF2, showed the same HSC phenotype. Unexpectedly, the robust cycling of HSCs lacking functional CYLD–TRAF2 interactions was not elicited by increased NF-κB signaling, but instead by increased activation of the p38MAPK pathway. Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD–TRAF2–p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.
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- 2015
4. Transcriptome-wide Profiling and Posttranscriptional Analysis of Hematopoietic Stem/Progenitor Cell Differentiation toward Myeloid Commitment
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Jeroen Krijgsveld, Nina Cabezas-Wallscheid, Andreas Trumpp, Daniel Klimmeck, Alejandro Reyes, Lisa von Paleske, Simon Renders, Jenny Hansson, and Wolfgang Huber
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Resource ,Myeloid ,Proteome ,Cellular differentiation ,Biology ,Biochemistry ,Transcriptome ,Genetics ,medicine ,Cell Adhesion ,Animals ,Cell Lineage ,Gene Regulatory Networks ,Myeloid Cells ,Progenitor cell ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Multipotent Stem Cells ,Cell Cycle ,Immunity ,Cell Differentiation ,Cell Biology ,Flow Cytometry ,Hematopoietic Stem Cells ,Cell biology ,Endothelial stem cell ,Mice, Inbred C57BL ,Haematopoiesis ,medicine.anatomical_structure ,Gene Ontology ,lcsh:Biology (General) ,Multipotent Stem Cell ,Female ,RNA, Long Noncoding ,Stem cell ,Energy Metabolism ,lcsh:Medicine (General) ,Developmental Biology - Abstract
Summary Hematopoietic stem cells possess lifelong self-renewal activity and generate multipotent progenitors that differentiate into lineage-committed and subsequently mature cells. We present a comparative transcriptome analysis of ex vivo isolated mouse multipotent hematopoietic stem/progenitor cells (LinnegSCA-1+c-KIT+) and myeloid committed precursors (LinnegSCA-1negc-KIT+). Our data display dynamic transcriptional networks and identify a stem/progenitor gene expression pattern that is characterized by cell adhesion and immune response components including kallikrein-related proteases. We identify 498 expressed lncRNAs, which are potential regulators of multipotency or lineage commitment. By integrating these transcriptome with our recently reported proteome data, we found evidence for posttranscriptional regulation of processes including metabolism and response to oxidative stress. Finally, our study identifies a high number of genes with transcript isoform regulation upon lineage commitment. This in-depth molecular analysis outlines the enormous complexity of expressed coding and noncoding RNAs and posttranscriptional regulation during the early differentiation steps of hematopoietic stem cells toward the myeloid lineage., Highlights • Transcriptional control and immune response pathways indicative of stem/progenitors • Identification of lncRNA species expressed during early adult hematopoiesis • Posttranscriptional regulation of oxidative stress response and metabolism • High degree of differential exon usage upon lineage commitment, In this article, Trumpp, Huber, and colleagues provide a comprehensive transcriptome and posttranscriptional analysis of hematopoietic stem/progenitor cell differentiation toward myeloid commitment. By integrating the proteome of these cells, they found evidence for posttranscriptional regulation in genes involved in metabolic stress response. They uncover lncRNA expression and transcript isoform changes upon commitment. All the data are available in an interactive website.
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- 2014
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5. Identification of DNA methylation changes atcis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing
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Carl Herrmann, Christoph Plass, Benedikt Brors, Dieter Weichenhan, Lei Gu, Peer Wünsche, Petra Zeisberger, Lisa von Paleske, Michael D. Milsom, Qi Wang, Andreas Trumpp, Daniel B. Lipka, Simon Haas, Simon Renders, Nina Cabezas-Wallscheid, Marieke Ag Essers, Daniel Klimmeck, Roland Eils, David Brocks, and Amelie Lier
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Genetics ,education.field_of_study ,Extra View ,Cellular differentiation ,Population ,Cell Differentiation ,Cell Biology ,Methylation ,DNA Methylation ,Regulatory Sequences, Nucleic Acid ,Biology ,Hematopoietic Stem Cells ,Malignant transformation ,Cell biology ,Haematopoiesis ,DNA methylation ,Humans ,Epigenetics ,Stem cell ,education ,Molecular Biology ,Developmental Biology - Abstract
Epigenetic alterations during cellular differentiation are a key molecular mechanism which both instructs and reinforces the process of lineage commitment. Within the haematopoietic system, progressive changes in the DNA methylome of haematopoietic stem cells (HSCs) are essential for the effective production of mature blood cells. Inhibition or loss of function of the cellular DNA methylation machinery has been shown to lead to a severe perturbation in blood production and is also an important driver of malignant transformation. HSCs constitute a very rare cell population in the bone marrow, capable of life-long self-renewal and multi-lineage differentiation. The low abundance of HSCs has been a major technological barrier to the global analysis of the CpG methylation status within both HSCs and their immediate progeny, the multipotent progenitors (MPPs). Within this Extra View article, we review the current understanding of how the DNA methylome regulates normal and malignant hematopoiesis. We also discuss the current methodologies that are available for interrogating the DNA methylation status of HSCs and MPPs and describe a new data set that was generated using tagmentation-based whole genome bisulfite sequencing (TWGBS) in order to comprehensively map methylated cytosines using the limited amount of genomic DNA that can be harvested from rare cell populations. Extended analysis of this data set clearly demonstrates the added value of genome-wide sequencing of methylated cytosines and identifies novel important cis-acting regulatory regions that are dynamically remodeled during the first steps of haematopoietic differentiation.
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- 2014
6. Author Correction: A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
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Veli Vural Uslu, Carsten Bahr, Massimo Petretich, Alex Murison, Roberta Scognamiglio, Peter W. Zandstra, Ido Amit, Mathieu Lupien, Stanley W.K. Ng, Naoya Takayama, Katja Langenfeld, François Spitz, Lisa von Paleske, Silvia Remeseiro, Petra Zeisberger, John E. Dick, Amelie S. Benk, and Andreas Trumpp
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0301 basic medicine ,Combinatorics ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,Multidisciplinary ,Stem cell ,Enhancer ,Mathematics - Abstract
In the originally published version of this Letter, ref. 43 was erroneously provided twice. In the 'Estimation of relative cell-type-specific composition of AML samples' section in the Methods, the citation to ref. 43 after the GEO dataset GSE24759 is correct. However, in the 'Mice' section of the Methods, the citation to ref. 43 after 'TAMERE' should have been associated with a new reference1. The original Letter has been corrected online (with the new reference included as ref. 49).
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- 2018
7. A Novel Enhancer Region 1.7Mb Downstream of the C-Myc Gene Drives Its Expression in Hematopoietic Stem and Progenitor Cells
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Andreas Trumpp, Veli Vural Uslu, Massimo Petretich, Lisa von Paleske, and François Spitz
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Immunology ,Hematopoietic stem cell ,Enhancer RNAs ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Null allele ,Molecular biology ,Haematopoiesis ,medicine.anatomical_structure ,medicine ,Progenitor cell ,Stem cell ,Enhancer ,Transcription factor - Abstract
The c-MYC transcription factor is a central regulator of cellular proliferation, growth, metabolism and differentiation in many cell types including stem cells (1). Although it is known that c-Myc expression is tightly controlled and can drive transformation if de-regulated, the mechanisms of its transcriptional regulation remain elusive. Besides its promoter, which is not sufficient to account for Myc endogenous expression, only a few cis-regulatory elements have been defined. c-Myc is located within a 4 Mb-long gene-poor region, which coincides with a large topologically associating domain (TAD) (2). At the distal end of this TAD, 1.7 Mb downstream of the mouse c-Myc gene, we identified a cluster of enhancer-associated chromatin marks which were present only in hematopoietic tissues. A LacZ reporter gene inserted next to this cluster showed specific expression in hematopoietic stem cells (HSCs) and progenitor cells. Mice homozygous for a deletion of this enhancer region showed decreased myeloid and B cells, while HSCs, multipotent progenitors and megakaryocytes accumulated in the bone marrow. This phenotype closely mimicked the phenotype of mice in which the c-Myc gene was conditionally deleted using Mx1-Cre (3). Importantly, gene expression analysis showed that the deletion of this enhancer region led to a dramatic reduction of Myc expression in HSCs, multipotent progenitors and most mature cell types. Furthermore, compound heterozygous mice carrying one enhancer deletion allele and one c-Myc null allele demonstrated very similar hematopoietic defects to that of homozygous c-Myc null mice, showing allelism between c-Myc and the enhancer region. Altogether, these data provide genetic evidence that this enhancer region directly controls, in cis, c-Myc expression in HSC/progenitor cells. As the region is composed of multiple modules, we examined the relative enrichment of the enhancer-associated H3K27ac mark by ChIP for the different modules in different hematopoietic lineages. This analysis suggested that selective enhancer elements contribute differently to c-Myc expression in either granulocytes or HSC/progenitors. Interestingly, this highly conserved enhancer region is focally amplified in a number of AML patients, suggesting that it may be a critical component driving the increased Myc expression found in leukemias. In summary, we identified a distant hematopoietic-specific enhancer region for c-Myc and provide data which supports its critical function as a key regulatory region in normal hematopoiesis and highlights a potential role in leukemic transformation. (1) Laurenti et al. (2008). Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 3(6): 611-624. (2) Dixon et al. (2012). Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398): 376-380. (3) Wilson et al. (2004). c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 18(22): 2747-2763. Disclosures No relevant conflicts of interest to declare.
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- 2014
8. The global RNA and protein landscape of hematopoietic stem cells and their immediate progeny
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Daniel B. Lipka, Daniel Klimmeck, Jenny Hansson, Wolfgang Huber, Qi Wang, Michael D. Milsom, Christoph Plass, Alejandro Reyes, Lisa von Paleske, Andreas Trumpp, Nina Cabezas-Wallscheid, and Jeroen Krijgsveld
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Cancer Research ,Haematopoiesis ,Genetics ,RNA ,Cell Biology ,Hematology ,Stem cell ,Biology ,Molecular Biology ,Virology - Published
- 2014
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