423 research outputs found
TFAP2C regulates transcription in human naive pluripotency by opening enhancers.
Naive and primed pluripotent human embryonic stem cells bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-seq and found enrichment of the activator protein-2 (AP2) transcription factor binding motif at naive-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naive reversion and becomes widespread at naive-specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naive by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naive-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naive human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse
MORC1 represses transposable elements in the mouse male germline
The Microrchidia (Morc) family of GHKL ATPases are present in a wide variety of prokaryotic and eukaryotic organisms but are of largely unknown function. Genetic screens in Arabidopsis thaliana have identified Morc genes as important repressors of transposons and other DNA-methylated and silent genes. MORC1-deficient mice were previously found to display male-specific germ cell loss and infertility. Here we show that MORC1 is responsible for transposon repression in the male germline in a pattern that is similar to that observed for germ cells deficient for the DNA methyltransferase homologue DNMT3L. Morc1 mutants show highly localized defects in the establishment of DNA methylation at specific classes of transposons, and this is associated with failed transposon silencing at these sites. Our results identify MORC1 as an important new regulator of the epigenetic landscape of male germ cells during the period of global de novo methylation
Robust estimation of fractal measures for characterizing the structural complexity of the human brain: optimization and reproducibility
High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the grey matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising, 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9–0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies
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Simultaneous deletion of Tet1 and Tet3 increases transcriptome variability in early embryogenesis
Dioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.J.K. was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. W.A.P. was supported by the National Science Foundation predoctoral graduate research fellowship while this work was being performed, and subsequently by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. L.C. was the recipient of a Feodor-Lynen fellowship from the Alexander von Humboldt foundation. M.L. is supported by the Max Planck Society within its International Max Planck Research School for Computational Biology and Scientific Computing program (IMPRS-CBSC). A.T. was the recipient of an Irvington postdoctoral fellowship from the Cancer Research Institute. This work was supported by NIH R01 Grants AI044432 and HD065812 (to A.R.) and a Director’s New Innovator Award (DP2-OD-008646-01) (to S.K.).This is the author accepted manuscript. The final version is available from The National Academy of Sciences via http://dx.doi.org/10.1073/pnas.151051011
Integrating technical debt into MDE
The main goal of this work is to evaluate the feasibility to
calculate the technical debt (a traditional software quality approach) in
a model-driven context through the same tools used by software deve-
lopers at work. The SonarQube tool was used, so that the quality check
was performed directly on projects created with Eclipse Modeling Frame-
work (EMF) instead of traditionals source code projects. In this work,
XML was used as the model speci cation language to verify in Sonar-
Qube due to the creation of EMF metamodels in XMI (XML Metadata
Interchange) and that SonarQube o ers a plugin to assess the XML lan-
guage. After this, our work focused on the de nition of model rules as
an XSD schema (XML Schema De nition) and the integration between
EMF-SonarQube in order that these metrics were directly validated by
SonarQube; and subsequently, this tool determined the technical debt
that the analyzed EMF models could containF. G, thanks to Colciencias (Colombia) for funding this work through the Colciencias Grant call 512-2010. This work has been supported by the Spanish MICINN PROS-Req (TIN2010-19130-C02-02), the Generalitat Valenciana Project ORCA (PROMETEO/2009/015), the European Commission FP7 Project CaaS (611351), and ERDF structural funds.Giraldo Velásquez, FD.; España Cubillo, S.; Pineda, MA.; Giraldo, WJ.; Pastor López, O. (2014). Integrating technical debt into MDE. CEUR Workshop Proceedings. http://hdl.handle.net/10251/68278
TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells
TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR)
TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells
TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR)
The Critical Juncture Concept’s Evolving Capacity to Explain Policy Change
This article examines the evolution of our understanding of the critical junctures concept. The concept finds its origins in historical intuitionalism, being employed in the context of path dependence to account for sudden and jarring institutional or policy changes. We argue that the concept and the literature surrounding it—now incorporating ideas, discourse, and agency—have gradually become more comprehensive and nuanced as historical institutionalism was followed by ideational historical institutionalism and constructivist and discursive institutionalism. The prime position of contingency has been supplanted by the role of ideas and agency in explaining critical junctures and other instances of less than transformative change. Consequently, the concept is now capable of providing more comprehensive explanations for policy change
Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea
A prominent epigenetic mechanism for gene regulation is methylation of cytosine bases in DNA. TET enzymes facilitate DNA demethylation by converting 5-methylcytosine (5mC) to oxidized methylcytosines (oxi-mCs). We show that oxi-mCs are generated by conserved TET/JBP enzymes encoded in the genome of the model organism Coprinopsis cinerea and present a method for simultaneous mapping of the three different species of oxi-mCs at near–base-pair resolution. We observe that centromeres and transposable elements exhibit distinctive patterns of 5mC and oxi-mC, and show that gene body 5mC and oxi-mC mark silent paralogous multicopy genes. Our study describes a method to map three species of oxi-mC simultaneously and reveals the colocation of 5mC and oxi-mC at functional elements throughout the C. cinerea genome
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