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1.
Genetics ; 224(4)2023 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-37210214

RESUMO

Metazoans guard their germlines against transposons and other foreign transcripts with PIWI-interacting RNAs (piRNAs). Due to the robust heritability of the silencing initiated by piRNAs in Caenorhabditis elegans (C. elegans), previous screens using C. elegans were strongly biased to uncover members of this pathway in the maintenance process but not in the initiation process. To identify novel piRNA pathway members, we have utilized a sensitized reporter strain which detects defects in initiation, amplification, or regulation of piRNA silencing. Using our reporter, we have identified Integrator complex subunits, nuclear pore components, protein import components, and pre-mRNA splicing factors as essential for piRNA-mediated gene silencing. We found the small nuclear processing cellular machine termed the Integrator complex is required for both type I and type II piRNA production. Notably, we identified a role for nuclear pore and nucleolar components NPP-1/Nup54, NPP-6/Nup160, NPP-7/Nup153, and FIB-1 in promoting the perinuclear localization of anti-silencing CSR-1 Argonaute, as well as a role for Importin factor IMA-3 in nuclear localization of silencing Argonaute HRDE-1. Together, we have shown that piRNA silencing in C. elegans is dependent on evolutionarily ancient RNA processing machinery that has been co-opted to function in the piRNA-mediated genome surveillance pathway.


Assuntos
Proteínas de Caenorhabditis elegans , Proteínas de Drosophila , Animais , RNA de Interação com Piwi , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Drosophila/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Inativação Gênica , Proteínas Argonautas/genética , Processamento Pós-Transcricional do RNA , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo
2.
Elife ; 92020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001031

RESUMO

Terminal selectors are transcription factors (TFs) that establish during development and maintain throughout life post-mitotic neuronal identity. We previously showed that UNC-3/Ebf, the terminal selector of C. elegans cholinergic motor neurons (MNs), acts indirectly to prevent alternative neuronal identities (Feng et al., 2020). Here, we globally identify the direct targets of UNC-3. Unexpectedly, we find that the suite of UNC-3 targets in MNs is modified across different life stages, revealing 'temporal modularity' in terminal selector function. In all larval and adult stages examined, UNC-3 is required for continuous expression of various protein classes (e.g. receptors, transporters) critical for MN function. However, only in late larvae and adults, UNC-3 is required to maintain expression of MN-specific TFs. Minimal disruption of UNC-3's temporal modularity via genome engineering affects locomotion. Another C. elegans terminal selector (UNC-30/Pitx) also exhibits temporal modularity, supporting the potential generality of this mechanism for the control of neuronal identity.


Assuntos
Neurônios Colinérgicos/fisiologia , Modelos Neurológicos , Neurônios Motores/fisiologia , Fatores de Transcrição , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Locomoção/genética , Locomoção/fisiologia , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Nat Commun ; 8(1): 1034, 2017 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-29044119

RESUMO

The WNT/ß-catenin signaling pathway is a prominent player in many developmental processes, including gastrulation, anterior-posterior axis specification, organ and tissue development, and homeostasis. Here, we use human pluripotent stem cells (hPSCs) to study the dynamics of the transcriptional response to exogenous activation of the WNT pathway. We describe a mechanism involving the WNT target gene SP5 that leads to termination of the transcriptional program initiated by WNT signaling. Integration of gene expression profiles of wild-type and SP5 mutant cells with genome-wide SP5 binding events reveals that SP5 acts to diminish expression of genes previously activated by the WNT pathway. Furthermore, we show that activation of SP5 by WNT signaling is most robust in cells with developmental potential, such as stem cells. These findings indicate a mechanism by which the developmental WNT signaling pathway reins in expression of transcriptional programs.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Células-Tronco Pluripotentes/metabolismo , Fatores de Transcrição/metabolismo , Proteína Wnt3A/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes/citologia , Fatores de Transcrição/genética , Via de Sinalização Wnt , Proteína Wnt3A/genética , beta Catenina/genética , beta Catenina/metabolismo
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