Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters

Synthetic small duplex RNAs that are fully complementary to gene promoters can silence transcription in mammalian cells. microRNAs (miRNAs) are endogenous small regulatory RNAs that sequence specifically regulate gene expression. We have developed a computational method to identify potential miRNA target sites within gene promoters. Ten candidate miRNAs predicted to target the human progesterone receptor (PR) gene promoter were tested for their ability to modulate gene expression. Several miRNA mimics inhibited PR gene expression and miR-423-5p, which targets a highly conserved region of the PR promoter, was chosen for detailed analysis. Chromatin immunoprecipitation revealed that the miR-423-5p mimic decreased RNA polymerase II occupancy and increased histone H3 lysine 9 dimethylation (H3K9me2) at the PR promoter, indicative of chromatin-level silencing. Transcriptional silencing was transient, independent of DNA methylation, and associated with recruitment of Argonaute 2 (AGO2) to a non-coding RNA (ncRNA) transcript that overlaps the PR gene promoter. The miR-423-5p mimic also silenced expression of immunoglobulin superfamily member 1 (IGSF1), an additional gene with a predicted target site within its promoter. While additional investigations of endogenous miRNA function will be necessary, these observations suggest that recognition of gene promoters by miRNAs may be a natural and general mechanism for regulating gene transcription

Molecular Gas in the z=1.2 Ultraluminous Merger GOODS J123634.53+621241.3

We report the detection of CO(2-1) emission from the z=1.2 ultraluminous infrared galaxy (ULIRG) GOODS J123634.53+621241.3 (also known as the sub-millimeter galaxy GN26). These observations represent the first discovery of high-redshift CO emission using the new Combined Array for Research in Millimeter-Wave Astronomy (CARMA). Of all high-redshift (z>1) galaxies within the GOODS-North field, this source has the largest far-infrared (FIR) flux observed in the Spitzer 70um and 160um bands. The CO redshift confirms the optical identification of the source, and the bright CO(2-1) line suggests the presence of a large molecular gas reservoir of about 7x10^10 M(sun). The infrared-to-CO luminosity ratio of L(IR)/L'(CO) = 80+/-30 L(sun) (K Km/s pc^2)^-1 is slightly smaller than the average ratio found in local ULIRGs and high-redshift sub-millimeter galaxies. The short star-formation time scale of about 70 Myr is consistent with a starburst associated with the merger event and is much shorter than the time scales for spiral galaxies and estimates made for high-redshift galaxies selected on the basis of their B-z and z-K colors.Comment: Accepted for publication in ApJ Letter

AzTEC Millimetre Survey of the COSMOS Field - II. Source Count Overdensity and Correlations with Large-Scale Structure

We report an over-density of bright sub-millimetre galaxies (SMGs) in the 0.15 sq. deg. AzTEC/COSMOS survey and a spatial correlation between the SMGs and the optical-IR galaxy density at z <~ 1.1. This portion of the COSMOS field shows a ~ 3-sigma over-density of robust SMG detections when compared to a background, or "blankfield", population model that is consistent with SMG surveys of fields with no extragalactic bias. The SMG over-density is most significant in the number of very bright detections (14 sources with measured fluxes S(1.1mm) > 6 mJy), which is entirely incompatible with sample variance within our adopted blank-field number densities and infers an over-density significance of >> 4. We find that the over-density and spatial correlation to optical-IR galaxy density are most consistent with lensing of a background SMG population by foreground mass structures along the line of sight, rather than physical association of the SMGs with the z <~ 1.1 galaxies/clusters. The SMG positions are only weakly correlated with weak-lensing maps, suggesting that the dominant sources of correlation are individual galaxies and the more tenuous structures in the region and not the massive and compact clusters. These results highlight the important roles cosmic variance and large-scale structure can play in the study of SMGs.Comment: 12 pages, 11 figures, 2 tables, accepted for publication in MNRA

AzTEC millimeter survey of the COSMOS field - III. Source catalog over 0.72 sq. deg. and plausible boosting by large-scale structure

We present a 0.72 sq. deg. contiguous 1.1mm survey in the central area of the COSMOS field carried out to a 1sigma ~ 1.26 mJy/beam depth with the AzTEC camera mounted on the 10m Atacama Submillimeter Telescope Experiment (ASTE). We have uncovered 189 candidate sources at a signal-to-noise ratio S/N >= 3.5, out of which 129, with S/N >= 4, can be considered to have little chance of being spurious (< 2 per cent). We present the number counts derived with this survey, which show a significant excess of sources when compared to the number counts derived from the ~0.5 sq. deg. area sampled at similar depths in the Scuba HAlf Degree Extragalactic Survey (SHADES, Austermann et al. 2010). They are, however, consistent with those derived from fields that were considered too small to characterize the overall blank-field population. We identify differences to be more significant in the S > 5 mJy regime, and demonstrate that these excesses in number counts are related to the areas where galaxies at redshifts z < 1.1 are more densely clustered. The positions of optical-IR galaxies in the redshift interval 0.6 < z < 0.75 are the ones that show the strongest correlation with the positions of the 1.1mm bright population (S > 5 mJy), a result which does not depend exclusively on the presence of rich clusters within the survey sampled area. The most likely explanation for the observed excess in number counts at 1.1mm is galaxy-galaxy and galaxy-group lensing at moderate amplification levels, that increases in amplitude as one samples larger and larger flux densities. This effect should also be detectable in other high redshift populations.Comment: 21 pages, 17 figures, accepted for publication in MNRA

Deep 1.1 mm-wavelength imaging of the GOODS-S field by AzTEC/ASTE - I. Source catalogue and number counts

[Abridged] We present the first results from a 1.1 mm confusion-limited map of the GOODS-S field taken with AzTEC on the ASTE telescope. We imaged a 270 sq. arcmin field to a 1\sigma depth of 0.48 - 0.73 mJy/beam, making this one of the deepest blank-field surveys at mm-wavelengths ever achieved. Although our GOODS-S map is extremely confused, we demonstrate that our source identification and number counts analyses are robust, and the techniques discussed in this paper are relevant for other deeply confused surveys. We find a total of 41 dusty starburst galaxies with S/N >= 3.5 within this uniformly covered region, where only two are expected to be false detections. We derive the 1.1mm number counts from this field using both a "P(d)" analysis and a semi-Bayesian technique, and find that both methods give consistent results. Our data are well-fit by a Schechter function model with (S', N(3mJy), \alpha) = (1.30+0.19 mJy, 160+27 (mJy/deg^2)^(-1), -2.0). Given the depth of this survey, we put the first tight constraints on the 1.1 mm number counts at S(1.1mm) = 0.5 mJy, and we find evidence that the faint-end of the number counts at S(850\mu m) < 2.0 mJy from various SCUBA surveys towards lensing clusters are biased high. In contrast to the 870 \mu m survey of this field with the LABOCA camera, we find no apparent under-density of sources compared to previous surveys at 1.1 mm. Additionally, we find a significant number of SMGs not identified in the LABOCA catalogue. We find that in contrast to observations at wavelengths < 500 \mu m, MIPS 24 \mu m sources do not resolve the total energy density in the cosmic infrared background at 1.1 mm, demonstrating that a population of z > 3 dust-obscured galaxies that are unaccounted for at these shorter wavelengths potentially contribute to a large fraction (~2/3) of the infrared background at 1.1 mm.Comment: 21 pages, 9 figures. Accepted to MNRAS

Integrative genomic analysis reveals widespread enhancer regulation by p53 in response to DNA damage

The tumor suppressor p53 has been studied extensively as a direct transcriptional activator of protein-coding genes. Recent studies, however, have shed light on novel regulatory functions of p53 within noncoding regions of the genome. Here, we use a systematic approach that integrates transcriptome-wide expression analysis, genome-wide p53 binding profiles and chromatin state maps to characterize the global regulatory roles of p53 in response to DNA damage. Notably, our approach identified conserved features of the p53 network in both human and mouse primary fibroblast models. In addition to known p53 targets, we identify many previously unappreciated mRNAs and long noncoding RNAs that are regulated by p53. Moreover, we find that p53 binding occurs predominantly within enhancers in both human and mouse model systems. The ability to modulate enhancer activity offers an additional layer of complexity to the p53 network and greatly expands the diversity of genomic elements directly regulated by p53

Detection of an ultra-bright submillimeter galaxy in the Subaru/XMM-Newton Deep Field using AzTEC/ASTE

We report the detection of an extremely bright ($\sim$37 mJy at 1100 $\mu$m and $\sim$91 mJy at 880 $\mu$m) submillimeter galaxy (SMG), AzTEC-ASTE-SXDF1100.001 (hereafter referred to as SXDF1100.001 or Orochi), discovered in 1100 $\mu$m observations of the Subaru/XMM-Newton Deep Field using AzTEC on ASTE. Subsequent CARMA 1300 $\mu$m and SMA 880 $\mu$m observations successfully pinpoint the location of Orochi and suggest that it has two components, one extended (FWHM of $\sim$ 4$^{\prime\prime}$) and one compact (unresolved). Z-Spec on CSO has also been used to obtain a wide band spectrum from 190 to 308 GHz, although no significant emission/absorption lines are found. The derived upper limit to the line-to-continuum flux ratio is 0.1--0.3 (2 $\sigma$) across the Z-Spec band. Based on the analysis of the derived spectral energy distribution from optical to radio wavelengths of possible counterparts near the SMA/CARMA peak position, we suggest that Orochi is a lensed, optically dark SMG lying at $z \sim 3.4$ behind a foreground, optically visible (but red) galaxy at $z \sim 1.4$. The deduced apparent (i.e., no correction for magnification) infrared luminosity ($L_{\rm IR}$) and star formation rate (SFR) are $6 \times 10^{13}$ $L_{\odot}$ and 11000 $M_{\odot}$ yr$^{-1}$, respectively, assuming that the $L_{\rm IR}$ is dominated by star formation. These values suggest that Orochi will consume its gas reservoir within a short time scale ($3 \times 10^{7}$ yr), which is indeed comparable to those in extreme starbursts like the centres of local ULIRGs.Comment: 18 pages, 13 figure

The source counts of submillimetre galaxies detected at 1.1 mm

The source counts of galaxies discovered at sub-millimetre and millimetre wavelengths provide important information on the evolution of infrared-bright galaxies. We combine the data from six blank-field surveys carried out at 1.1 mm with AzTEC, totalling 1.6 square degrees in area with root-mean-square depths ranging from 0.4 to 1.7 mJy, and derive the strongest constraints to date on the 1.1 mm source counts at flux densities S(1100) = 1-12 mJy. Using additional data from the AzTEC Cluster Environment Survey to extend the counts to S(1100) ~ 20 mJy, we see tentative evidence for an enhancement relative to the exponential drop in the counts at S(1100) ~ 13 mJy and a smooth connection to the bright source counts at >20 mJy measured by the South Pole Telescope; this excess may be due to strong lensing effects. We compare these counts to predictions from several semi-analytical and phenomenological models and find that for most the agreement is quite good at flux densities > 4 mJy; however, we find significant discrepancies (>3sigma) between the models and the observed 1.1 mm counts at lower flux densities, and none of them are consistent with the observed turnover in the Euclidean-normalised counts at S(1100) < 2 mJy. Our new results therefore may require modifications to existing evolutionary models for low luminosity galaxies. Alternatively, the discrepancy between the measured counts at the faint end and predictions from phenomenological models could arise from limited knowledge of the spectral energy distributions of faint galaxies in the local Universe.Comment: 16 pages, 3 figures, 4 tables; accepted for publication in MNRA

Evidence for a population of high-redshift submillimeter galaxies from interferometric imaging

We have used the Submillimeter Array to image a flux-limited sample of seven submillimeter galaxies, selected by the AzTEC camera on the JCMT at 1.1 mm, in the COSMOS field at 890 μ m with ~2\u27\u27 resolution. All of the sources—two radio-bright and five radio-dim—are detected as single point sources at high significance (\u3e6 σ), with positions accurate to ~0.2\u27\u27 that enable counterpart identification at other wavelengths observed with similarly high angular resolution. All seven have IRAC counterparts, but only two have secure counterparts in deep HST ACS imaging. As compared to the two radio-bright sources in the sample, and those in previous studies, the five radio-dim sources in the sample (1) have systematically higher submillimeter-to-radio flux ratios, (2) have lower IRAC 3.6-8.0 μ m fluxes, and (3) are not detected at 24 μ m . These properties, combined with size constraints at 890 μ m (θ 1.2\u27\u27), suggest that the radio-dim submillimeter galaxies represent a population of very dusty starbursts, with physical scales similar to local ultraluminous infrared galaxies, with an average redshift higher than radio-bright sources

The AzTEC/SMA Interferometric Imaging Survey of Submillimeter-Selected High-Redshift Galaxies

We present results from a continuing interferometric survey of high-redshift submillimeter galaxies with the Submillimeter Array, including high-resolution (beam size ~2 arcsec) imaging of eight additional AzTEC 1.1mm selected sources in the COSMOS Field, for which we obtain six reliable (peak S/N>5 or peak S/N>4 with multiwavelength counterparts within the beam) and two moderate significance (peak S/N>4) detections. When combined with previous detections, this yields an unbiased sample of millimeter-selected SMGs with complete interferometric followup. With this sample in hand, we (1) empirically confirm the radio-submillimeter association, (2) examine the submillimeter morphology - including the nature of submillimeter galaxies with multiple radio counterparts and constraints on the physical scale of the far infrared - of the sample, and (3) find additional evidence for a population of extremely luminous, radio-dim submillimeter galaxies that peaks at higher redshift than previous, radio-selected samples. In particular, the presence of such a population of high-redshift sources has important consequences for models of galaxy formation - which struggle to account for such objects even under liberal assumptions - and dust production models given the limited time since the Big Bang.Comment: 11 pages, 7 figures, accepted for publication in Ap