Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

The glucocorticoid receptor (GR) affects the transcription of genes involved in diverse processes, including energy metabolism and the immune response, through DNA-binding dependent and independent mechanisms. The DNA-binding dependent mechanism occurs by direct binding of GR to glucocorticoid response elements (GREs) at regulatory regions of target genes. The DNA-binding independent mechanism involves binding of GR to transcription factors and coactivators that, in turn, contact DNA. A small molecule that competes with GR for binding to GREs could be expected to affect the DNA-dependent pathway selectively by interfering with the protein-DNA interface. We show that a DNA-binding polyamide that targets the consensus GRE sequence binds the glucocorticoid-induced zipper (GILZ) GRE, inhibits expression of GILZ and several other known GR target genes, and reduces GR occupancy at the GILZ promoter. Genome-wide expression analysis of the effects of this polyamide on a set of glucocorticoid-induced and -repressed genes could help to elucidate the mechanism of GR regulation for these genes

Lyman Alpha Blobs as an Observational Signature of Cold Accretion Streams into Galaxies

Recent hydrodynamic simulations of galaxy formation reveal streams of cold (T ~ 1e4 K) gas flowing into the centers of dark matter halos as massive as 1e12-1e13.5 M_sun at redshifts z~1-3. In this paper we show that if > 20% of the gravitational binding energy of the gas is radiated away, then the simulated cold flows are spatially extended Lyman Alpha (Lya) sources with luminosities, Lya line widths, and number densities that are comparable to those of observed Lya blobs. Furthermore, the filamentary structure of the cold flows can explain the wide range of observed Lya blob morphologies. Since the most massive halos form in dense environments, the association of Lya blobs with overdense regions arise naturally. We argue that Lya blobs - even those which are clearly associated with starburst galaxies or quasars - provide direct observational support for the cold accretion mode of galaxies. We discuss various testable predictions of this association.Comment: MNRAS in press. 13 pages, 6 figures. Discussion + references added. Main conclusions unaffecte

The Late Reionization of Filaments

We study the topology of reionization using accurate three-dimensional radiative transfer calculations post-processed on outputs from cosmological hydrodynamic simulations. In our simulations, reionization begins in overdense regions and then "leaks" directly into voids, with filaments reionizing last owing to their combination of high recombination rate and low emissivity. This result depends on the uniquely-biased emissivity field predicted by our prescriptions for star formation and feedback, which have previously been shown to account for a wide array of measurements of the post-reionization Universe. It is qualitatively robust to our choice of simulation volume, ionizing escape fraction, and spatial resolution (in fact it grows stronger at higher spatial resolution) even though the exact overlap redshift is sensitive to each of these. However, it weakens slightly as the escape fraction is increased owing to the reduced density contrast at higher redshift. We also explore whether our results are sensitive to commonly-employed approximations such as using optically-thin Eddington tensors or substantially altering the speed of light. Such approximations do not qualitatively change the topology of reionization. However, they can systematically shift the overlap redshift by up to $\Delta z\sim 0.5$, indicating that accurate radiative transfer is essential for computing reionization. Our model cannot simultaneously reproduce the observed optical depth to Thomson scattering and ionization rate per hydrogen atom at $z=6$, which could owe to numerical effects and/or missing early sources of ionization.Comment: 16 pages, 9 figures, accepted to MNRA

GeV Gamma-Ray Attenuation and the High-Redshift UV Background

We present new calculations of the evolving UV background out to the epoch of cosmological reionization and make predictions for the amount of GeV gamma-ray attenuation by electron-positron pair production. Our results are based on recent semi-analytic models of galaxy formation, which provide predictions of the dust-extinguished UV radiation field due to starlight, and empirical estimates of the contribution due to quasars. We account for the reprocessing of ionizing photons by the intergalactic medium. We test whether our models can reproduce estimates of the ionizing background at high redshift from flux decrement analysis and proximity effect measurements from quasar spectra, and identify a range of models that can satisfy these constraints. Pair-production against soft diffuse photons leads to a spectral cutoff feature for gamma rays observed between 10 and 100 GeV. This cutoff varies with redshift and the assumed star formation and quasar evolution models. We find only negligible amounts of absorption for gamma rays observed below 10 GeV for any emission redshift. With observations of high-redshift sources in sufficient numbers by the Fermi Gamma-ray Space Telescope and new ground-based instruments it should be possible to constrain the extragalactic background light in the UV and optical portion of the spectrum.Comment: 19 pages, 12 figures, Accepted for publication in MNRAS, this version includes minor correction

The orphan receptor ERRα interferes with steroid signaling

The estrogen receptor-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily that has been shown to interfere with the estrogen-signaling pathway. In this report, we demonstrate that ERRα also cross-talks with signaling driven by other steroid hormones. Treatment of human prostatic cells with a specific ERRα inverse agonist reduces the expression of several androgen-responsive genes, in a manner that does not involve perturbation of androgen receptor expression or activity. Furthermore, ERRα activates the expression of androgen response elements (ARE)-containing promoters, such as that of the prostate cancer marker PSA, in an ARE-dependent manner. In addition, promoters containing a steroid response element can be activated by all members of the ERR orphan receptor subfamily, and this, even in the presence of antisteroid compounds