Anosov representations and proper actions

We establish several characterizations of Anosov representations of word hyperbolic groups into real reductive Lie groups, in terms of a Cartan projection or Lyapunov projection of the Lie group. Using a properness criterion of Benoist and Kobayashi, we derive applications to proper actions on homogeneous spaces of reductive groups.Comment: 73 pages, 4 figures; to appear in Geometry & Topolog

The LIM domain protein nTRIP6 acts as a co-repressor for the transcription factor MEF2C in myoblasts

The transcription factor Myocyte enhancer factor 2C (MEF2C) plays a key role in the late differentiation of skeletal muscle progenitor cells, the so-called myoblasts. During myoblast differentiation, both MEF2C expression and transcriptional activity are regulated. We have reported that nTRIP6, the nuclear isoform of the focal adhesion LIM domain protein TRIP6, acts as an adaptor transcriptional co-activator for several transcription factors. It interacts with the promoter-bound transcription factors and consequently mediates the recruitment of other co-activators. Based on a described interaction between MEF2C and TRIP6 in a yeast-two-hybrid screen, we hypothesised a co-regulatory function of nTRIP6 for MEF2C. In proliferating myoblasts, nTRIP6 interacted with MEF2C and was recruited together with MEF2C to the MEF2-binding regions of the MEF2C target genes Myom2, Mb, Tnni2 and Des. Silencing nTRIP6 or preventing its interaction with MEF2C increased MEF2C transcriptional activity and increased the expression of these MEF2C target genes. Thus, nTRIP6 acts as a co-repressor for MEF2C. Mechanistically, nTRIP6 mediated the recruitment of the class IIa histone deacetylase HDAC5 to the MEF2C-bound promoters. In conclusion, our results unravel a transcriptional co-repressor function for nTRIP6. This adaptor co-regulator can thus exert either co-activator or co-repressor functions, depending on the transcription factor it interacts with

Protein-Functionalized DNA Nanostructures as Tools to Control Transcription in Zebrafish Embryos

The unique structure-directing properties of DNA origami nanostructures (DONs) show great potential to specifically manipulate intracellular processes. We report an innovative concept to selectively activate the transcription of a single gene in the developing zebrafish embryo. We reason that engineering a designer transcription factor in which a rigid DON imposes a fixed distance between the DNA-binding domain (DBD) and the transactivation domain (TAD) would allow the selective activation of a gene harboring the same distance between the corresponding transcription factor binding site and the core promoter. As a test case, a rigid tubular DON was designed to separate the DBD of the GAL4 transcription factor and the VP16 viral protein as a TAD. This construct was microinjected in the yolk of one-cell-stage zebrafish embryos, together with a reporter plasmid to assess its functionality. The large DON was efficiently distributed to cells of the developing embryo and showed no signs of toxicity. However, because the DON showed only a cytosolic localization, it did not activate transcription of the reporter gene. Although this work clearly demonstrates that DON microinjection enables the intracellular distribution of multi-protein architectures in most of the cells of the developing zebrafish embryo, further refinements are necessary to enable selective gene activation in vivo

TRIP6 functions in brain ciliogenesis

TRIP6, a member of the ZYXIN-family of LIM domain proteins, is a focal adhesion compo- nent. Trip6 deletion in the mouse, reported here, reveals a function in the brain: ependymal and choroid plexus epithelial cells are carrying, unexpectedly, fewer and shorter cilia, are poorly differentiated, and the mice develop hydrocephalus. TRIP6 carries numerous protein interaction domains and its functions require homodimerization. Indeed, TRIP6 disruption in vitro (in a choroid plexus epithelial cell line), via RNAi or inhibition of its homodimerization, confirms its function in ciliogenesis. Using super-resolution microscopy, we demonstrate TRIP6 localization at the pericentriolar material and along the ciliary axoneme. The requirement for homodimerization which doubles its interaction sites, its punctate localiza- tion along the axoneme, and its co-localization with other cilia components suggest a scaf- fold/co-transporter function for TRIP6 in cilia. Thus, this work uncovers an essential role of a LIM-domain protein assembly factor in mammalian ciliogenesis

Anosov representations: Domains of discontinuity and applications

The notion of Anosov representations has been introduced by Labourie in his study of the Hitchin component for SL(n,R). Subsequently, Anosov representations have been studied mainly for surface groups, in particular in the context of higher Teichmueller spaces, and for lattices in SO(1,n). In this article we extend the notion of Anosov representations to representations of arbitrary word hyperbolic groups and start the systematic study of their geometric properties. In particular, given an Anosov representation of $\Gamma$ into G we explicitly construct open subsets of compact G-spaces, on which $\Gamma$ acts properly discontinuously and with compact quotient. As a consequence we show that higher Teichmueller spaces parametrize locally homogeneous geometric structures on compact manifolds. We also obtain applications regarding (non-standard) compact Clifford-Klein forms and compactifications of locally symmetric spaces of infinite volume.Comment: 63 pages, accepted for publication in Inventiones Mathematica

Insights on Glucocorticoid Receptor Activity Modulation through the Binding of Rigid Steroids

Background: The glucocorticoid receptor (GR) is a transcription factor that regulates gene expression in a ligand-dependent fashion. This modular protein is one of the major pharmacological targets due to its involvement in both cause and treatment of many human diseases. Intense efforts have been made to get information about the molecular basis of GR activity. Methodology/Principal Findings: Here, the behavior of four GR-ligand complexes with different glucocorticoid and antiglucocorticoid properties were evaluated. The ability of GR-ligand complexes to oligomerize in vivo was analyzed by performing the novel Number and Brightness assay. Results showed that most of GR molecules form homodimers inside the nucleus upon ligand binding. Additionally, in vitro GR-DNA binding analyses suggest that ligand structure modulates GRDNA interaction dynamics rather than the receptor's ability to bind DNA. On the other hand, by coimmunoprecipitation studies we evaluated the in vivo interaction between the transcriptional intermediary factor 2 (TIF2) coactivator and different GR-ligand complexes. No correlation was found between GR intranuclear distribution, cofactor recruitment and the homodimerization process. Finally, Molecular determinants that support the observed experimental GR LBD-ligand/TIF2 interaction were found by Molecular Dynamics simulation. Conclusions/Significance: The data presented here sustain the idea that in vivo GR homodimerization inside the nucleus can be achieved in a DNA-independent fashion, without ruling out a dependent pathway as well. Moreover, since at least one GR-ligand complex is able to induce homodimer formation while preventing TIF2 coactivator interaction, results suggest that these two events might be independent from each other. Finally, 21-hydroxy-6,19-epoxyprogesterone arises as a selective glucocorticoid with potential pharmacological interest. Taking into account that GR homodimerization and cofactor recruitment are considered essential steps in the receptor activation pathway, results presented here contribute to understand how specific ligands influence GR behavior. © 2010 Presman et al.Fil:Presman, D.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Alvarez, L.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Levi, V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Measurement of the Splitting Function in &ITpp &ITand Pb-Pb Collisions at root&ITsNN&IT=5.02 TeV

Data from heavy ion collisions suggest that the evolution of a parton shower is modified by interactions with the color charges in the dense partonic medium created in these collisions, but it is not known where in the shower evolution the modifications occur. The momentum ratio of the two leading partons, resolved as subjets, provides information about the parton shower evolution. This substructure observable, known as the splitting function, reflects the process of a parton splitting into two other partons and has been measured for jets with transverse momentum between 140 and 500 GeV, in pp and PbPb collisions at a center-of-mass energy of 5.02 TeV per nucleon pair. In central PbPb collisions, the splitting function indicates a more unbalanced momentum ratio, compared to peripheral PbPb and pp collisions.. The measurements are compared to various predictions from event generators and analytical calculations.Peer reviewe