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  1. Article ; Online: A theoretical model of Polycomb/Trithorax action unites stable epigenetic memory and dynamic regulation.

    Reinig, Jeannette / Ruge, Frank / Howard, Martin / Ringrose, Leonie

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 4782

    Abstract: Polycomb and Trithorax group proteins maintain stable epigenetic memory of gene expression states for some genes, but many targets show highly dynamic regulation. Here we combine experiment and theory to examine the mechanistic basis of these different ... ...

    Abstract Polycomb and Trithorax group proteins maintain stable epigenetic memory of gene expression states for some genes, but many targets show highly dynamic regulation. Here we combine experiment and theory to examine the mechanistic basis of these different modes of regulation. We present a mathematical model comprising a Polycomb/Trithorax response element (PRE/TRE) coupled to a promoter and including Drosophila developmental timing. The model accurately recapitulates published studies of PRE/TRE mediated epigenetic memory of both silencing and activation. With minimal parameter changes, the same model can also recapitulate experimental data for a different PRE/TRE that allows dynamic regulation of its target gene. The model predicts that both cell cycle length and PRE/TRE identity are critical for determining whether the system gives stable memory or dynamic regulation. Our work provides a simple unifying framework for a rich repertoire of PRE/TRE functions, and thus provides insights into  genome-wide Polycomb/Trithorax regulation.
    MeSH term(s) Animals ; Cell Division ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/physiology ; Epigenesis, Genetic ; Epigenomics ; Female ; Gene Expression Regulation, Developmental/genetics ; Gene Silencing ; Models, Theoretical ; Polycomb Repressive Complex 1/genetics ; Polycomb Repressive Complex 1/metabolism ; Polycomb-Group Proteins/metabolism ; Promoter Regions, Genetic ; Response Elements
    Chemical Substances Chromosomal Proteins, Non-Histone ; DNA-Binding Proteins ; Drosophila Proteins ; Pc protein, Drosophila ; Polycomb-Group Proteins ; trx protein, Drosophila ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
    Language English
    Publishing date 2020-09-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-18507-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

    Kaltenecker, Doris / Spirk, Katrin / Ruge, Frank / Grebien, Florian / Herling, Marco / Rupprecht, Anne / Kenner, Lukas / Pohl, Elena E / Mueller, Kristina M / Moriggl, Richard

    Molecular metabolism

    2020  Volume 40, Page(s) 101026

    Abstract: Objective: Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until ... ...

    Abstract Objective: Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until now several members of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway have been implicated as being relevant for BAT physiology. However, whether the STAT family member STAT5 is important for the thermogenic property of adipose tissues is unknown. Therefore, we have investigated the role of STAT5 in thermogenic fat in this paper.
    Methods: We performed metabolic and molecular analyses using mice that harbor an adipocyte-specific deletion of Stat5a/b alleles.
    Results: We found that STAT5 is necessary for acute cold-induced temperature maintenance and the induction of lipid mobilization in BAT following β
    Conclusion: We conclude that STAT5 is essential for the functionality and the β-adrenergic responsiveness of thermogenic adipose tissue.
    MeSH term(s) Adipocytes/metabolism ; Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Animals ; Cold-Shock Response/physiology ; Energy Metabolism ; Female ; Lipid Metabolism/physiology ; Lipids/physiology ; Lipolysis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Obesity/metabolism ; Receptors, Adrenergic, beta/metabolism ; Receptors, Adrenergic, beta/physiology ; STAT5 Transcription Factor/metabolism ; STAT5 Transcription Factor/physiology ; Thermogenesis/physiology
    Chemical Substances Lipids ; Receptors, Adrenergic, beta ; STAT5 Transcription Factor ; Stat5a protein, mouse
    Language English
    Publishing date 2020-05-28
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2020.101026
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  3. Article ; Online: Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.

    Suske, Tobias / Sorger, Helena / Manhart, Gabriele / Ruge, Frank / Prutsch, Nicole / Zimmerman, Mark W / Eder, Thomas / Abdallah, Diaaeldin I / Maurer, Barbara / Wagner, Christina / Schönefeldt, Susann / Spirk, Katrin / Pichler, Alexander / Pemovska, Tea / Schweicker, Carmen / Pölöske, Daniel / Hubanic, Emina / Jungherz, Dennis / Müller, Tony Andreas /
    Aung, Myint Myat Khine / Orlova, Anna / Pham, Ha Thi Thanh / Zimmel, Kerstin / Krausgruber, Thomas / Bock, Christoph / Müller, Mathias / Dahlhoff, Maik / Boersma, Auke / Rülicke, Thomas / Fleck, Roman / de Araujo, Elvin Dominic / Gunning, Patrick Thomas / Aittokallio, Tero / Mustjoki, Satu / Sanda, Takaomi / Hartmann, Sylvia / Grebien, Florian / Hoermann, Gregor / Haferlach, Torsten / Staber, Philipp Bernhard / Neubauer, Heidi Anne / Look, Alfred Thomas / Herling, Marco / Moriggl, Richard

    The Journal of clinical investigation

    2024  Volume 134, Issue 8

    Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the ...

    Abstract T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
    MeSH term(s) Animals ; Humans ; Mice ; Mice, Transgenic ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Protein-Tyrosine Kinases ; Receptors, Antigen, T-Cell/genetics ; Signal Transduction ; STAT5 Transcription Factor/genetics
    Chemical Substances Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptors, Antigen, T-Cell ; STAT5 Transcription Factor ; STAT5B protein, human ; STAT5A protein, human
    Language English
    Publishing date 2024-04-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI168536
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  4. Article ; Online: Tc-knirps plays different roles in the specification of antennal and mandibular parasegment boundaries and is regulated by a pair-rule gene in the beetle Tribolium castaneum.

    Peel, Andrew D / Schanda, Julia / Grossmann, Daniela / Ruge, Frank / Oberhofer, Georg / Gilles, Anna F / Schinko, Johannes B / Klingler, Martin / Bucher, Gregor

    BMC developmental biology

    2013  Volume 13, Page(s) 25

    Abstract: Background: The Drosophila larval head is evolutionarily derived at the genetic and morphological level. In the beetle Tribolium castaneum, development of the larval head more closely resembles the ancestral arthropod condition. Unlike in Drosophila, a ... ...

    Abstract Background: The Drosophila larval head is evolutionarily derived at the genetic and morphological level. In the beetle Tribolium castaneum, development of the larval head more closely resembles the ancestral arthropod condition. Unlike in Drosophila, a knirps homologue (Tc-kni) is required for development of the antennae and mandibles. However, published Tc-kni data are restricted to cuticle phenotypes and Tc-even-skipped and Tc-wingless stainings in knockdown embryos. Hence, it has remained unclear whether the entire antennal and mandibular segments depend on Tc-kni function, and whether the intervening intercalary segment is formed completely. We address these questions with a detailed examination of Tc-kni function.
    Results: By examining the expression of marker genes in RNAi embryos, we show that Tc-kni is required only for the formation of the posterior parts of the antennal and mandibular segments (i.e. the parasegmental boundaries). Moreover, we find that the role of Tc-kni is distinct in these segments: Tc-kni is required for the initiation of the antennal parasegment boundary, but only for the maintenance of the mandibular parasegmental boundary. Surprisingly, Tc-kni controls the timing of expression of the Hox gene Tc-labial in the intercalary segment, although this segment does form in the absence of Tc-kni function. Unexpectedly, we find that the pair-rule gene Tc-even-skipped helps set the posterior boundary of Tc-kni expression in the mandible. Using the mutant antennaless, a likely regulatory Null mutation at the Tc-kni locus, we provide evidence that our RNAi studies represent a Null situation.
    Conclusions: Tc-kni is required for the initiation of the antennal and the maintenance of the mandibular parasegmental boundaries. Tc-kni is not required for specification of the anterior regions of these segments, nor the intervening intercalary segment, confirming that Tc-kni is not a canonical 'gap-gene'. Our finding that a gap gene orthologue is regulated by a pair rule gene adds to the view that the segmentation gene hierarchies differ between Tribolium and Drosophila upstream of the pair rule gene level. In Tribolium, as in Drosophila, head and trunk segmentation gene networks cooperate to pattern the mandibular segment, albeit involving Tc-kni as novel component.
    MeSH term(s) Animals ; Coleoptera/genetics ; Mandible/growth & development ; Phenotype
    Language English
    Publishing date 2013-06-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1471-213X
    ISSN (online) 1471-213X
    DOI 10.1186/1471-213X-13-25
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  5. Article ; Online: Pharmacologic inhibition of STAT5 in acute myeloid leukemia.

    Wingelhofer, Bettina / Maurer, Barbara / Heyes, Elizabeth C / Cumaraswamy, Abbarna A / Berger-Becvar, Angelika / de Araujo, Elvin D / Orlova, Anna / Freund, Patricia / Ruge, Frank / Park, Jisung / Tin, Gary / Ahmar, Siawash / Lardeau, Charles-Hugues / Sadovnik, Irina / Bajusz, Dávid / Keserű, György Miklós / Grebien, Florian / Kubicek, Stefan / Valent, Peter /
    Gunning, Patrick T / Moriggl, Richard

    Leukemia

    2018  Volume 32, Issue 5, Page(s) 1135–1146

    Abstract: The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid ... ...

    Abstract The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4-130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD
    MeSH term(s) Animals ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Synergism ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Pyrazoles/pharmacology ; STAT5 Transcription Factor/antagonists & inhibitors ; Terpenes/pharmacology ; fms-Like Tyrosine Kinase 3
    Chemical Substances Pyrazoles ; STAT5 Transcription Factor ; Terpenes ; ruxolitinib (82S8X8XX8H) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; garcinol (TR1VR1V71B)
    Language English
    Publishing date 2018-02-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-017-0005-9
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2295: Show issues Location:
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  6. Article ; Online: A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element.

    Herzog, Veronika A / Lempradl, Adelheid / Trupke, Johanna / Okulski, Helena / Altmutter, Christina / Ruge, Frank / Boidol, Bernd / Kubicek, Stefan / Schmauss, Gerald / Aumayr, Karin / Ruf, Marius / Pospisilik, Andrew / Dimond, Andrew / Senergin, Hasene Basak / Vargas, Marcus L / Simon, Jeffrey A / Ringrose, Leonie

    Nature genetics

    2014  Volume 46, Issue 9, Page(s) 973–981

    Abstract: Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila ... ...

    Abstract Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. We propose that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription.
    MeSH term(s) Animals ; Base Sequence ; Binding Sites ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/genetics ; DNA-Binding Proteins/genetics ; Drosophila Proteins/genetics ; Drosophila melanogaster ; Genes, Switch ; Genome, Insect ; Histone-Lysine N-Methyltransferase/genetics ; Molecular Sequence Data ; Polycomb-Group Proteins/genetics ; RNA, Untranslated ; Response Elements ; Transcription Factors/genetics ; Transcription, Genetic
    Chemical Substances Chromatin ; Chromosomal Proteins, Non-Histone ; DNA-Binding Proteins ; Drosophila Proteins ; Polycomb-Group Proteins ; RNA, Untranslated ; Transcription Factors ; trx protein, Drosophila ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; PRC2 protein, Drosophila (EC 2.1.1.43)
    Language English
    Publishing date 2014-08-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.3058
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    Zs.A 3613: Show issues Location:
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