The green-striped forest looper on Vancouver Island

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Genomic mapping of RNA polymerase II reveals sites of co-transcriptional regulation in human cells

BACKGROUND: Transcription by RNA polymerase II is regulated at many steps including initiation, promoter release, elongation and termination. Accumulation of RNA polymerase II at particular locations across genes can be indicative of sites of regulation. RNA polymerase II is thought to accumulate at the promoter and at sites of co-transcriptional alternative splicing where the rate of RNA synthesis slows. RESULTS: To further understand transcriptional regulation at a global level, we determined the distribution of RNA polymerase II within regions of the human genome designated by the ENCODE project. Hypophosphorylated RNA polymerase II localizes almost exclusively to 5' ends of genes. On the other hand, localization of total RNA polymerase II reveals a variety of distinct landscapes across many genes with 74% of the observed enriched locations at exons. RNA polymerase II accumulates at many annotated constitutively spliced exons, but is biased for alternatively spliced exons. Finally, RNA polymerase II is also observed at locations not in gene regions. CONCLUSION: Localizing RNA polymerase II across many millions of base pairs in the human genome identifies novel sites of transcription and provides insights into the regulation of transcription elongation. These data indicate that RNA polymerase II accumulates most often at exons during transcription. Thus, a major factor of transcription elongation control in mammalian cells is the coordination of transcription and pre-mRNA processing to define exons

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. CONCLUSIONS: The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).Supported by a grant (R01HL082945) from the National Institutes of Health (NIH), the Edward P. Evans Foundation, the Leukemia and Lymphoma Society, and the Howard Hughes Faculty Scholars Program (to Dr. Ebert); a grant (5T32HL116324, to Dr. Jaiswal) from the NIH and a Burroughs Wellcome Career Award for Medical Sciences; the John S. LaDue Memorial Fellowship in Cardiology at Harvard Medical School (to Dr. Natarajan); the Ofer and Shelly Nemirovsky MGH Research Scholar Award (to Dr. Kathiresan); a grant (5U54HG003067, to Dr. Gabriel) from the NIH; a grant (R01-HL080472, to Dr. Libby) from the NIH and the RRM Charitable Fund; a grant (G0800270) from the U.K. Medical Research Council, a grant (SP/09/002) from the British Heart Foundation, the U.K. National Institute for Health Research Cambridge Biomedical Research Centre, a grant (268834) from the European Research Council, and a grant (HEALTH-F2-2012-279233) from the European Commission Framework Program 7 (all to Dr. Danesh); and grants from the National Heart, Lung, and Blood Institute, Pfizer, Regeneron, Eli Lilly, and Genentech (to Dr. Saleheen). Fieldwork and biochemical assays in PROMIS were funded through the University of Cambridge by the British Heart Foundation, U.K. Medical Research Council, Wellcome Trust, European Union Framework 6–funded Bloodomics Integrated Project, Pfizer, Novartis, Merck, the Center for Non-Communicable Diseases (in Pakistan), by project grants (RC2HL101834 and RC1TW008485) from the NIH, and by a grant (RC1TW008485) from the Fogarty International Center

Hole Doping Evolution of the Quasiparticle Band in Models of Strongly Correlated Electrons for the High-T_c Cuprates

Quantum Monte Carlo (QMC) and Maximum Entropy (ME) techniques are used to study the spectral function $A({\bf p},\omega)$ of the one band Hubbard model in strong coupling including a next-nearest-neighbor electronic hopping with amplitude $t'/t= -0.35$. These values of parameters are chosen to improve the comparison of the Hubbard model with angle-resolved photoemission (ARPES) data for $Sr_2 Cu O_2 Cl_2$. A narrow quasiparticle (q.p.) band is observed in the QMC analysis at the temperature of the simulation $T=t/3$, both at and away from half-filling. Such a narrow band produces a large accumulation of weight in the density of states at the top of the valence band. As the electronic density $$ decreases further away from half-filling, the chemical potential travels through this energy window with a large number of states, and by $\sim 0.70$ it has crossed it entirely. The region near momentum $(0,\pi)$ and $(\pi,0)$ in the spectral function is more sensitive to doping than momenta along the diagonal from $(0,0)$ to $(\pi,\pi)$. The evolution with hole density of the quasiparticle dispersion contains some of the features observed in recent ARPES data in the underdoped regime. For sufficiently large hole densities the ``flat'' bands at $(\pi,0)$ cross the Fermi energy, a prediction that could be tested with ARPES techniques applied to overdoped cuprates. The population of the q.p. band introduces a {\it hidden} density in the system which produces interesting consequences when the quasiparticles are assumed to interact through antiferromagnetic fluctuations and studied with the BCS gap equation formalism. In particular, a region of extended s-wave is found to compete with d-wave in the overdoped regime, i.e. when the chemical potential has almost entirely crossed the q.p.Comment: 14 pages, Revtex, with 13 embedded ps figures, submitted to Phys. Rev. B., minor modifications in the text and in figures 1b, 2b, 3b, 4b, and 6

Interlocking Transcriptional Feedback Loops Control White-Opaque Switching in Candida albicans

The human pathogen Candida albicans can assume either of two distinct cell types, designated “white” and “opaque.” Each cell type is maintained for many generations; switching between them is rare and stochastic, and occurs without any known changes in the nucleotide sequence of the genome. The two cell types differ dramatically in cell shape, colony appearance, mating competence, and virulence properties. In this work, we investigate the transcriptional circuitry that specifies the two cell types and controls the switching between them. First, we identify two new transcriptional regulators of white-opaque switching, Czf1 and white-opaque regulator 2 (Wor2). Analysis of a large set of double mutants and ectopic expression strains revealed genetic relationships between CZF1, WOR2, and two previously identified regulators of white-opaque switching, WOR1 and EFG1. Using chromatin immunoprecipitation, we show that Wor1 binds the intergenic regions upstream of the genes encoding three additional transcriptional regulators of white-opaque switching (CZF1, EFG1, and WOR2), and also occupies the promoters of numerous white- and opaque-enriched genes. Based on these interactions, we have placed these four genes in a circuit controlling white-opaque switching whose topology is a network of positive feedback loops, with the master regulator gene WOR1 occupying a central position. Our observations indicate that a key role of the interlocking feedback loop network is to stably maintain each epigenetic state through many cell divisions

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal