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First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor (2017)

Moody, James D. ; Levy, Shiri ; Mathieu, Julie ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2017; 114(38): 10125-10130. Published 2017 Sep 01. doi: 10.1073/pnas.1706907114.

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Publikationsdatum: 2017-09-01

Beschreibung: The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate recognition functions of PRC2 are coupled by binding of the N-terminal helix of the Ezh2 methylase to an extended groove on the EED trimethyl lysine binding subunit. Disrupting PRC2 function can in principle be achieved by blocking this single interaction, but there are few approaches for blocking specific protein–protein interactions in living cells and organisms. Here, we describe the computational design of proteins that bind to the EZH2 interaction site on EED with subnanomolar affinity in vitro and form tight and specific complexes with EED in living cells. Induction of the EED binding proteins abolishes H3K27 methylation in human embryonic stem cells (hESCs) and at all but the earliest stage blocks self-renewal, pinpointing the first critical repressive H3K27me3 marks in development.

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Damming the rivers of the Amazon basin (2017)

Edgardo M. Latrubesse; Eugenio Y. Arima; Thomas Dunne; Edward Park; Victor R. Baker; Fernando M. d’Horta; Charles Wight; Florian Wittmann; Jansen Zuanon; Paul A. Baker; Camila C. Ribas; Richard B. Norgaard; Naziano Filizola; Atif Ansar; Bent Flyvbjerg; Jose C. Stevaux

Springer Nature

In: Nature

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Publikationsdatum: 2017-06-15

Beschreibung: Damming the rivers of the Amazon basin Nature 546, 7658 (2017). doi:10.1038/nature22333 Authors: Edgardo M. Latrubesse, Eugenio Y. Arima, Thomas Dunne, Edward Park, Victor R. Baker, Fernando M. d’Horta, Charles Wight, Florian Wittmann, Jansen Zuanon, Paul A. Baker, Camila C. Ribas, Richard B. Norgaard, Naziano Filizola, Atif Ansar, Bent Flyvbjerg & Jose C. Stevaux More than a hundred hydropower dams have already been built in the Amazon basin and numerous proposals for further dam constructions are under consideration. The accumulated negative environmental effects of existing dams and proposed dams, if constructed, will trigger massive hydrophysical and biotic disturbances that

Print ISSN: 0028-0836

Digitale ISSN: 1476-4687

Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor [Developmental Biology] (2017)

James D. Moody, Shiri Levy, Julie Mathieu, Yalan Xing, Woojin Kim, Cheng Dong, Wolfram Tempel, Aaron M. Robitaille, Luke T. Dang, Amy Ferreccio, Damien Detraux, Sonia Sidhu, Licheng Zhu, Lauren Carter, Chao Xu, Cristina Valensisi, Yuliang Wang, R. David Hawkins, Jinrong Min, Randall T. Moon, Stuart H. Orkin, David Baker, Hannele Ruohola-Baker

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publikationsdatum: 2017-09-20

Beschreibung: The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate...

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Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Amino-acids in Nectar and their Evolutionary Significance (1973)

BAKER, H. G. ; BAKER, IRENE

Springer Nature

In: Nature. 1973; 241(5391): 543-545. Published 1973 Feb 01. doi: 10.1038/241543b0.

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Publikationsdatum: 1973-02-01

Print ISSN: 0028-0836

Digitale ISSN: 1476-4687

Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik

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Slowed Movement Stopping in Parkinson’s Disease and Focal Dystonia is Improved by Standard Treatment (2019)

Choudhury, Supriyo ; Roy, Akash ; Mondal, Banashree ; [weitere]

Springer Nature

In: Scientific Reports. 2019; 9(1): 19504. Published 2019 Dec 01. doi: 10.1038/s41598-019-55321-5.

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Publikationsdatum: 2019-12-01

Digitale ISSN: 2045-2322

Thema: Allgemeine Naturwissenschaft

Publiziert von Springer Nature

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Damming the rivers of the Amazon basin (2017)

Latrubesse, Edgardo M. ; Arima, Eugenio Y. ; Dunne, Thomas ; [weitere]

Springer Nature

In: Nature. 2017; 546(7658): 363-369. Published 2017 Jun 01. doi: 10.1038/nature22333.

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Publikationsdatum: 2017-06-01

Print ISSN: 0028-0836

Digitale ISSN: 1476-4687

Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik

Publiziert von Springer Nature

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Gating machinery of InsP3R channels revealed by electron cryomicroscopy (2015)

Fan, Guizhen ; Baker, Matthew L. ; Wang, Zhao ; [weitere]

Springer Nature

In: Nature. 2015; 527(7578): 336-341. Published 2015 Oct 12. doi: 10.1038/nature15249.

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Publikationsdatum: 2015-10-12

Print ISSN: 0028-0836

Digitale ISSN: 1476-4687

Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik

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8

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Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis (2016)

Kudinov, Alexander E. ; Deneka, Alexander ; Nikonova, Anna S. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2016; 113(25): 6955-6960. Published 2016 Jun 06. doi: 10.1073/pnas.1513616113.

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Publikationsdatum: 2016-06-06

Beschreibung: Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of KrasLA1/+;P53R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial–mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial–mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria (2018)

Strangward, Patrick ; Haley, Michael J. ; Albornoz, Manuel G. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(28): 7404-7409. Published 2018 Jun 28. doi: 10.1073/pnas.1801737115.

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Publikationsdatum: 2018-06-28

Beschreibung: Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1β production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1β release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33–NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.

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Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Constraints on the evolution of a doublesex target gene arising from doublesex’s pleiotropic deployment (2015)

Luo, Shengzhan D. ; Baker, Bruce S.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(8): E852-E861. Published 2015 Feb 09. doi: 10.1073/pnas.1501192112.

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Publikationsdatum: 2015-02-09

Beschreibung: “Regulatory evolution,” that is, changes in a gene’s expression pattern through changes at its regulatory sequence, rather than changes at the coding sequence of the gene or changes of the upstream transcription factors, has been increasingly recognized as a pervasive evolution mechanism. Many somatic sexually dimorphic features of Drosophila melanogaster are the results of gene expression regulated by the doublesex (dsx) gene, which encodes sex-specific transcription factors (DSXF in females and DSXM in males). Rapid changes in such sexually dimorphic features are likely a result of changes at the regulatory sequence of the target genes. We focused on the Flavin-containing monooxygenase-2 (Fmo-2) gene, a likely direct dsx target, to elucidate how sexually dimorphic expression and its evolution are brought about. We found that dsx is deployed to regulate the Fmo-2 transcription both in the midgut and in fat body cells of the spermatheca (a female-specific tissue), through a canonical DSX-binding site in the Fmo-2 regulatory sequence. In the melanogaster group, Fmo-2 transcription in the midgut has evolved rapidly, in contrast to the conserved spermathecal transcription. We identified two cis-regulatory modules (CRM-p and CRM-d) that direct sexually monomorphic or dimorphic Fmo-2 transcription, respectively, in the midguts of these species. Changes of Fmo-2 transcription in the midgut from sexually dimorphic to sexually monomorphic in some species are caused by the loss of CRM-d function, but not the loss of the canonical DSX-binding site. Thus, conferring transcriptional regulation on a CRM level allows the regulation to evolve rapidly in one tissue while evading evolutionary constraints posed by other tissues.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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