Co-Regulation of Histone-Modifying Enzymes in Cancer

Cancer is characterized by aberrant patterns of expression of multiple genes. These major shifts in gene expression are believed to be due to not only genetic but also epigenetic changes. The epigenetic changes are communicated through chemical modifications, including histone modifications. However, it is unclear whether the binding of histone-modifying proteins to genomic regions and the placing of histone modifications efficiently discriminates corresponding genes from the rest of the genes in the human genome. We performed gene expression analysis of histone demethylases (HDMs) and histone methyltransferases (HMTs), their target genes and genes with relevant histone modifications in normal and tumor tissues. Surprisingly, this analysis revealed the existence of correlations in the expression levels of different HDMs and HMTs. The observed HDM/HMT gene expression signature was specific to particular normal and cancer cell types and highly correlated with target gene expression and the expression of genes with histone modifications. Notably, we observed that trimethylation at lysine 4 and lysine 27 separated preferentially expressed and underexpressed genes, which was strikingly different in cancer cells compared to normal cells. We conclude that changes in coordinated regulation of enzymes executing histone modifications may underlie global epigenetic changes occurring in cancer

Genome-wide Analysis using ChIP to Identify Isoform-specific Gene Targets

Recruitment of transcriptional and epigenetic factors to their targets is a key step in their regulation. Prominently featured in recruitment are the protein domains that bind to specific histone modifications. One such domain is the plant homeodomain (PHD), found in several chromatin-binding proteins. The epigenetic factor RBP2 has multiple PHD domains, however, they have different functions (Figure 4). In particular, the C-terminal PHD domain, found in a RBP2 oncogenic fusion in human leukemia, binds to trimethylated lysine 4 in histone H3 (H3K4me3)1. The transcript corresponding to the RBP2 isoform containing the C-terminal PHD accumulates during differentiation of promonocytic, lymphoma-derived, U937 cells into monocytes2. Consistent with both sets of data, genome-wide analysis showed that in differentiated U937 cells, the RBP2 protein gets localized to genomic regions highly enriched for H3K4me33. Localization of RBP2 to its targets correlates with a decrease in H3K4me3 due to RBP2 histone demethylase activity and a decrease in transcriptional activity. In contrast, two other PHDs of RBP2 are unable to bind H3K4me3. Notably, the C-terminal domain PHD of RBP2 is absent in the smaller RBP2 isoform4. It is conceivable that the small isoform of RBP2, which lacks interaction with H3K4me3, differs from the larger isoform in genomic location. The difference in genomic location of RBP2 isoforms may account for the observed diversity in RBP2 function. Specifically, RBP2 is a critical player in cellular differentiation mediated by the retinoblastoma protein (pRB). Consistent with these data, previous genome-wide analysis, without distinction between isoforms, identified two distinct groups of RBP2 target genes: 1) genes bound by RBP2 in a manner that is independent of differentiation; 2) genes bound by RBP2 in a differentiation-dependent manner

Absolute polarization angle calibration using polarized diffuse Galactic emission observed by BICEP

We present a method of cross-calibrating the polarization angle of a polarimeter using BICEP Galactic observations. \bicep\ was a ground based experiment using an array of 49 pairs of polarization sensitive bolometers observing from the geographic South Pole at 100 and 150 GHz. The BICEP polarimeter is calibrated to +/-0.01 in cross-polarization and less than +/-0.7 degrees in absolute polarization orientation. BICEP observed the temperature and polarization of the Galactic plane (R.A= 100 degrees ~ 270 degrees and Dec. = -67 degrees ~ -48 degrees). We show that the statistical error in the 100 GHz BICEP Galaxy map can constrain the polarization angle offset of WMAP Wband to 0.6 degrees +\- 1.4 degrees. The expected 1 sigma errors on the polarization angle cross-calibration for Planck or EPIC are 1.3 degrees and 0.3 degrees at 100 and 150 GHz, respectively. We also discuss the expected improvement of the BICEP Galactic field observations with forthcoming BICEP2 and Keck observations.Comment: 13 pages, 10 figures and 2 tables. To appear in Proceedings of SPIE Astronomical Telescopes and Instrumentation 201

The Grizzly, November 1, 1994

Presidential Search Enters Final Phase • Long Term and Short Term Goals Established by SSG • The United States Prison Population Reaches One Million • American Military Expansion in the Middle East on the Rise • Politics Department to Hold Roundtable Discussion • North Penn Teachers Enter Third Week of Strike • Campus Bids Farewell to Security Officer • U Phi D: Pride in the Name of Sisterhood • Young Alumni Planning Board • ProTheatre to Present Execution of Justice • Soccer Nears Endhttps://digitalcommons.ursinus.edu/grizzlynews/1345/thumbnail.jp

The South Atlantic Anticyclone as a key player for the representation of the tropical Atlantic climate in coupled climate models

The key role of the South Atlantic Anticyclone (SAA) on the seasonal cycle of the tropical Atlantic is investigated with a regionally coupled atmosphere–ocean model for two different coupled domains. Both domains include the equatorial Atlantic and a large portion of the northern tropical Atlantic, but one extends southward, and the other northwestward. The SAA is simulated as internal model variability in the former, and is prescribed as external forcing in the latter. In the first case, the model shows significant warm biases in sea surface temperature (SST) in the Angola-Benguela front zone. If the SAA is externally prescribed, these biases are substantially reduced. The biases are both of oceanic and atmospheric origin, and are influenced by ocean–atmosphere interactions in coupled runs. The strong SST austral summer biases are associated with a weaker SAA, which weakens the winds over the southeastern tropical Atlantic, deepens the thermocline and prevents the local coastal upwelling of colder water. The biases in the basins interior in this season could be related to the advection and eddy transport of the coastal warm anomalies. In winter, the deeper thermocline and atmospheric fluxes are probably the main biases sources. Biases in incoming solar radiation and thus cloudiness seem to be a secondary effect only observed in austral winter. We conclude that the external prescription of the SAA south of 20°S improves the simulation of the seasonal cycle over the tropical Atlantic, revealing the fundamental role of this anticyclone in shaping the climate over this region

Characterization of the BICEP Telescope for High-precision Cosmic Microwave Background Polarimetry

The Background Imaging of Cosmic Extragalactic Polarization (BICEP) experiment was designed specifically to search for the signature of inflationary gravitational waves in the polarization of the cosmic microwave background (CMB). Using a novel small-aperture refractor and 49 pairs of polarization-sensitive bolometers, BICEP has completed three years of successful observations at the South Pole beginning in 2006 February. To constrain the amplitude of the inflationary B-mode polarization, which is expected to be at least 7 orders of magnitude fainter than the 3 K CMB intensity, precise control of systematic effects is essential. This paper describes the characterization of potential systematic errors for the BICEP experiment, supplementing a companion paper on the initial cosmological results. Using the analysis pipelines for the experiment, we have simulated the impact of systematic errors on the B-mode polarization measurement. Guided by these simulations, we have established benchmarks for the characterization of critical instrumental properties including bolometer relative gains, beam mismatch, polarization orientation, telescope pointing, sidelobes, thermal stability, and timestream noise model. A comparison of the benchmarks with the measured values shows that we have characterized the instrument adequately to ensure that systematic errors do not limit BICEP's two-year results, and identifies which future refinements are likely necessary to probe inflationary B-mode polarization down to levels below a tensor-to-scalar ratio r = 0.1.Astronom

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Installing hydrolytic activity into a completely <i>de novo </i>protein framework

The design of enzyme-like catalysts tests our understanding of sequence-to-structure/function relationships in proteins. Here we install hydrolytic activity predictably into a completely de novo and thermostable α-helical barrel, which comprises seven helices arranged around an accessible channel. We show that the lumen of the barrel accepts 21 mutations to functional polar residues. The resulting variant, which has cysteine–histidine–glutamic acid triads on each helix, hydrolyses p-nitrophenyl acetate with catalytic efficiencies that match the most-efficient redesigned hydrolases based on natural protein scaffolds. This is the first report of a functional catalytic triad engineered into a de novo protein framework. The flexibility of our system also allows the facile incorporation of unnatural side chains to improve activity and probe the catalytic mechanism. Such a predictable and robust construction of truly de novo biocatalysts holds promise for applications in chemical and biochemical synthesis

Ideas and perspectives: strengthening the biogeosciences in environmental research networks

Many scientific approaches are improving our understanding and management of the rapidly changing environment. Long-term environmental research networks are one approach to advancing local, regional, and global environmental science and education. A remarkable number and wide variety of environmental research networks operate around the world today. These are diverse in funding, infrastructure, motivating questions, scientific strengths, and the sciences that birthed and maintained the networks. Some networks have individual sites that were selected because they had produced invaluable long-term data, while other networks have new sites selected to span ecological gradients. However, all long-term environmental networks share two challenges. Networks must keep pace with scientific advances and interact with both the scientific community and society at large. If networks fall short of successfully addressing these challenges, they risk becoming irrelevant. The objective of this paper is to assert that the biogeosciences offer environmental research networks a number of opportunities to expand scientific impact and public engagement. We explore some of these opportunities with four networks: the International Long Term Ecological Research programs (ILTERs), the Critical Zone Observatories (CZOs), the Earth and Ecological Observatory networks (EONs), and the FLUXNET program of eddy flux sites. While these networks were founded and grown by interdisciplinary scientists, the preponderance of expertise and funding have gravitated activities of ILTERs and EONs toward ecology and biology, CZOs toward the Earth sciences and geology, and FLUXNET toward ecophysiology and micrometeorology. Our point is not to homogenize networks, nor to diminish disciplinary science. Rather, we argue that by more fully incorporating the integration of biology and geology in long-term environmental research networks, scientists can better leverage network assets, keep pace with the ever-changing science of the environment, and engage with larger scientific and public audiences