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1.
Cell ; 181(7): 1661-1679.e22, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32526207

RESUMO

The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Microbioma Gastrointestinal/fisiologia , Microbiota/efeitos dos fármacos , Adulto , Animais , Bactérias/classificação , Biomarcadores Farmacológicos/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Voluntários Saudáveis , Humanos , Masculino , Metagenoma/genética , Metagenômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/genética , Preparações Farmacêuticas/metabolismo , Medicina de Precisão/métodos , RNA Ribossômico 16S/genética
2.
Development ; 138(16): 3431-40, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21752933

RESUMO

Asymmetric mRNA localization is an effective mechanism for establishing cellular and developmental polarity. Posterior localization of oskar in the Drosophila oocyte targets the synthesis of Oskar to the posterior, where Oskar initiates the assembly of the germ plasm. In addition to harboring germline determinants, the germ plasm is required for localization and translation of the abdominal determinant nanos. Consequently, failure of oskar localization during oogenesis results in embryos lacking germ cells and abdominal segments. oskar accumulates at the oocyte posterior during mid-oogenesis through a well-studied process involving kinesin-mediated transport. Through live imaging of oskar mRNA, we have uncovered a second, mechanistically distinct phase of oskar localization that occurs during late oogenesis and results in amplification of the germ plasm. Analysis of two newly identified oskar localization factors, Rumpelstiltskin and Lost, that are required specifically for this late phase of oskar localization shows that germ plasm amplification ensures robust abdomen and germ cell formation during embryogenesis. In addition, our results indicate the importance of mechanisms for adapting mRNAs to utilize multiple localization pathways as necessitated by the dramatic changes in ovarian physiology that occur during oogenesis.


Assuntos
Proteínas de Transporte/metabolismo , Citoplasma/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Oogênese , Alelos , Animais , Proteínas de Transporte/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Feminino , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Ligação Proteica , RNA Mensageiro/genética
3.
bioRxiv ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38370680

RESUMO

Changes in the gut microbiome have been associated with several human diseases, but the molecular and functional details underlying these associations remain largely unknown. Here, we performed a multi-cohort analysis of small molecule biosynthetic gene clusters (BGCs) in 5,306 metagenomic samples of the gut microbiome from 2,033 Inflammatory Bowel Disease (IBD) patients and 833 matched healthy subjects and identified a group of Clostridia-derived BGCs that are significantly associated with IBD. Using synthetic biology, we discovered and solved the structures of six fatty acid amides as the products of the IBD-enriched BGCs. Using two mouse models of colitis, we show that the discovered small molecules disrupt gut permeability and exacerbate inflammation in chemically and genetically susceptible mice. These findings suggest that microbiome-derived small molecules may play a role in the etiology of IBD and represent a generalizable approach for discovering molecular mediators of microbiome-host interactions in the context of microbiome-associated diseases.

4.
Dev Cell ; 10(3): 291-301, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16516833

RESUMO

Patterning of the anterior-posterior body axis of the Drosophila embryo requires production of Nanos protein selectively in the posterior. Spatially restricted Nanos synthesis is accomplished by translational repression of unlocalized nanos mRNA together with translational activation of posteriorly localized nanos. Repression of unlocalized nanos mRNA is mediated by a bipartite translational control element (TCE) in its 3' untranslated region. TCE stem-loop II functions during embryogenesis, through its interaction with the Smaug repressor. Stem-loop III represses unlocalized nanos mRNA during oogenesis, but trans-acting factors that carry out this function have remained elusive. Here we identify a Drosophila hnRNP, Glorund, that interacts specifically with stem-loop III. We establish that the ability of the TCE to repress translation in vivo reflects its ability to bind Glorund in vitro. These data, together with the analysis of a glorund null mutant, reveal a specific role for an hnRNP in repression of nanos translation during oogenesis.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Biossíntese de Proteínas , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Padronização Corporal , Proteínas de Drosophila/genética , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Oócitos/citologia , Oócitos/metabolismo , Oogênese/fisiologia , Ovário/citologia , Ovário/fisiologia , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/genética , Alinhamento de Sequência
5.
Mech Dev ; 125(1-2): 81-90, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18036786

RESUMO

The development of a functional germline is essential for species propagation. The nanos (nos) gene plays an evolutionarily conserved role in germline development and is also essential for abdominal patterning in Drosophila. A small fraction of nos mRNA is localized to the germ plasm at the posterior pole of the Drosophila embryo, where it becomes incorporated into the germ cells. Germ plasm associated nos mRNA is translated to produce a gradient of Nos protein that patterns the abdomen, whereas the remaining unlocalized RNA is translationally repressed to allow anterior development. Using transgenes that compromise nos mRNA localization and translational regulation, we show that wild-type body patterning can ensue without nos mRNA localization provided that nos translation is properly modulated. In contrast, localization of nos to the germ plasm, but not translational regulation, is essential for nos function in the developing germ cells. We propose that an imperative for nos localization in producing a functional germline has preserved an inefficient localization mechanism.


Assuntos
Padronização Corporal , Proteínas de Drosophila/genética , Drosophila/embriologia , Células Germinativas/citologia , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Animais , Northern Blotting , Hibridização In Situ , Biossíntese de Proteínas
6.
Cell Rep ; 19(1): 150-161, 2017 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-28380354

RESUMO

The Drosophila hnRNP F/H homolog, Glorund (Glo), regulates nanos mRNA translation by interacting with a structured UA-rich motif in the nanos 3' untranslated region. Glo regulates additional RNAs, however, and mammalian homologs bind G-tract sequences to regulate alternative splicing, suggesting that Glo also recognizes G-tract RNA. To gain insight into how Glo recognizes both structured UA-rich and G-tract RNAs, we used mutational analysis guided by crystal structures of Glo's RNA-binding domains and identified two discrete RNA-binding surfaces that allow Glo to recognize both RNA motifs. By engineering Glo variants that favor a single RNA-binding mode, we show that a subset of Glo's functions in vivo is mediated solely by the G-tract binding mode, whereas regulation of nanos requires both recognition modes. Our findings suggest a molecular mechanism for the evolution of dual RNA motif recognition in Glo that may be applied to understanding the functional diversity of other RNA-binding proteins.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Oócitos/metabolismo , Ovário/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Animais , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Feminino , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/química , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Mutação , Motivos de Nucleotídeos , Biossíntese de Proteínas , RNA/química , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Fator de Crescimento Transformador alfa/genética , Fator de Crescimento Transformador alfa/metabolismo
7.
Dev Biol ; 282(1): 207-17, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15936341

RESUMO

Developmental control of translation is frequently mediated by regulatory elements that reside within 3' untranslated regions (3' UTRs). Two stem-loops within the nanos 3' UTR translational control element (TCE) act independently to direct translational repression of maternal nanos mRNA in the ovary or embryo. We have previously shown that the nanos TCE can also function in select somatic sites. Using an ectopic expression screen, we now identify a new site of TCE function, the dorsal pouch epithelium. Analysis of TCE mutants reveals that TCE activity in the dorsal pouch does not depend on either of the stem-loops required for maternal TCE function, but instead requires a third feature-a sequence that closely matches the Bearded box, a regulatory motif found in the 3' UTRs of several Notch pathway genes. In addition, we identify pleiohomeotic mRNA as an endogenous candidate for regulation by Bearded box-like motifs in the dorsal pouch. Together, these results suggest that the TCE has appropriated a conserved regulatory motif to expand its function to somatic tissues.


Assuntos
Regiões 3' não Traduzidas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/genética , Embrião não Mamífero/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Biossíntese de Proteínas/fisiologia , Proteínas de Ligação a RNA/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Animais Geneticamente Modificados , Sequência de Bases , Cruzamentos Genéticos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/genética , Embrião não Mamífero/metabolismo , Epitélio/embriologia , Epitélio/metabolismo , Componentes do Gene , Hibridização In Situ , Dados de Sequência Molecular , Proteínas do Grupo Polycomb , Fatores de Transcrição/metabolismo , Transgenes/genética
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