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In vivo regulators of neural stem cell development and function
Full text linkNeural stem cells in the brain give rise to both neurons and glia cells during embryonic development and help maintain tissue homeostasis in adulthood. Although transcription factors and intracellular signaling pathways that modulate NSC function in embryonic and adult brain have been heavily studied, in vivo functions of long noncoding RNAs (lncRNAs) and chromatin regulators in NSCs are still poorly understood. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. In the embryonic cortex, I found that Pnky deletion increases neuronal differentiation and depletes NSCs prematurely, resulting in defects in cortical laminar structure in postnatal mice. Pnky expression from a bacterial artificial chromosome (BAC) transgene rescues the in vivo phenotypes of Pnky-deleted brains, supporting the idea that Pnky acts in trans as a key regulator of NSC function and neurogenesis in the embryonic cortex. Chromatin regulator JMJD3 is a histone demethylase implicated in development and disease of multiple organs. My studies show that Jmjd3-deletion in the hippocampus results in depletion of adult NSCs. During development, Jmjd3-deleted dentate gyrus precursors precociously differentiate into neurons, resulting in failed establishment of the hippocampal NSC niche. Single cell RNA-sequencing reveals a broad disruption of genes involved in maintaining stem cell function in Jmjd3-deleted NSCs. In the adult brain, loss of Jmjd3 similarly leads to precocious neuronal differentiation, reflecting the loss of gene expression signatures related to stem cell maintenance. These data indicate both lncRNA-Pnky and JMJD3 may control the rate of neurogenesis, acting like a cell-intrinsic clock for NSCs
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A single-cell sensor reveals spatial and temporal regulation of heterochromatin domain formation
Full text linkCell type specification in multicellular systems is due, at least in part, to differential access to and usage of the genomic DNA which is common to all cells, leading to cell type specific gene expression. This genomic pattern in enacted through the formation of gene-repressive heterochromatin, a nuclear ultrastructure, which silences transcription of genes embedded in the underlying DNA that are orthogonal to the intended cell fate and expands progressively, in a process known as spreading, while cells proceed through lineage commitment. Importantly, once the cell type specific pattern of gene expression has been established, it must be recapitulated over repeated cell division to ensure faithful maintenance of cell identity and avoid disease. Both the mechanisms which direct this process of differential expansion and the features of heterochromatin domains which are critical to its robust inheritance have not been fully elucidated. Utilizing a genetically tractable fission yeast model that recapitulates features of the metazoan chromatin environment, we interrogated the requirements for spatial and temporal regulation of heterochromatin domain formation. We find that at cell identity loci, robust gene silencing and the capacity to remember heterochromatin states over repeated division requires the collaboration of multiple sequence elements with distinct spreading properties and capacities to resist chromatin perturbations. Additionally, we find chromatin context dependent requirements for genetic regulation of the spreading process. Lastly, we described a mechanism for regulating the spatial expansion of heterochromatin domains that relies on the mutually antagonistic signals and properties that differ between hetero- and eu- chromatin domains
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Activation of Histone 3 Lysine 9 methyl writing and reading capabilities within the G9a-GLP heterodimer
Full text linkUnique among metazoan repressive histone methyltransferases, G9a and GLP, which target histone 3 lysine 9 (H3K9), require dimerization for productive H3K9 mono (me1)- and dimethylation (me2) in vivo. Intriguingly, even though each enzyme can independently methylate H3K9, the predominant active form in vivo is a heterodimer of G9a and GLP. How dimerization influences the central H3K9 methyl binding (“reading”) and deposition (“writing”) activity of G9a and GLP, and why heterodimerization is essential in vivo remains opaque. Here, we examine the H3K9me “reading” and “writing” activities of defined, recombinantly produced homo- and heterodimers of G9a and GLP. We find that both reading and writing are significantly enhanced in the heterodimer. Compared to the homodimers, the heterodimer has higher recognition of H3K9me2, and a striking ~ 10-fold increased kcat for nucleosomal substrates under multiple turnover conditions, which is not evident on histone tail peptide substrates. This however is not encoded by altered nucleosome affinity, which is dominated by the G9a protomer and comparable across the homo- and heterodimer. Our results indicate that heterodimerization may be required to relieve autoinhibition of H3K9me reading and chromatin methylation evident in G9a and GLP homodimers. Relieving this inhibition may be particularly important in early differentiation when large tracts of H3K9me2 are deposited by G9a-GLP, which may require a more active form of the enzyme
Molecular convergence of clock and photosensory pathways through PIF3–TOC1 interaction and co-occupancy of target promoters
Full text linkThis study defines a molecular mechanism for how clock- and light-signaling pathways converge in Arabidopsis. The data reveal that TOC1, an essential core component of the central oscillator, binds to and represses PIF transcriptional activators, which are also the direct molecular signaling partners of the phytochrome photosensory receptors. This finding shows that TOC1 functions as a clock output-transducer, directly linking the core oscillator to a pleiotopically-acting transcriptional network, through repression of target genes. Collectively, in the plant, these components comprise a transcriptionallycentered signaling hub that provides clock-imposed gating of PIF-mediated, photosensory-regulated diurnal growth patterns. These results provide a framework for future research aimed at understanding how circadian dynamics are integrated with other plant physiological processes important for optimal plant fitness.Fil: Soy, Judit. Universitat Autònoma de Barcelona; EspañaFil: Leivar, Pablo. Universitat Autònoma de Barcelona; EspañaFil: Gonzalez Schain, Nahuel Damian. Universitat Autònoma de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Martín, Guiomar. Universitat Autònoma de Barcelona; EspañaFil: Diaz, Céline. Universitat Autònoma de Barcelona; EspañaFil: Sentandreu, Maria. Universitat Autònoma de Barcelona; EspañaFil: Al-Sady, Bassem. University of California at Berkeley; Estados Unidos. United States Department of Agriculture; Estados UnidosFil: Quail, Peter H.. University of California at Berkeley; Estados Unidos. United States Department of Agriculture; Estados UnidosFil: Monte, Elena. Universitat Autònoma de Barcelona; Españ
Epigenetic fates of gene silencing established by heterochromatin spreading in cell identity and genome stability
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Epigenetic fates of gene silencing established by heterochromatin spreading in cell identity and genome stability.
Full text linkHeterochromatin spreading, the propagation of repressive chromatin along the chromosome, is a reaction critical to genome stability and defense, as well as maintenance of unique cell fates. Here, we discuss the intrinsic properties of the spreading reaction and circumstances under which its products, formed distal to DNA-encoded nucleation sites, can be epigenetically maintained. Finally, we speculate that the epigenetic properties of heterochromatin evolved together with the need to stabilize cellular identity
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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