Understanding the mechanisms of IGF2 gene regulation in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. HCC has a very well studied etiology, and is associated with chronic hepatic viral infections (hepatitis viruses B and C), alcohol abuse, or other causes of chronic liver damage. Currently, tumor resection and liver transplantation are the only potentially curative treatments available for HCC. However, the presence of extra-hepatic invasion and metastasis makes patients ineligible for these treatments. High IGF2 levels are associated with metastatic HCC, and we recently showed that IGF2-induced signaling through Igf1R stimulates the invasiveness and metastatic phenotype of HCC cells. However, the precise mechanisms by which IGF2 expression is enhanced in HCC are not well understood. IGF2 is an imprinted gene normally expressed from the paternal allele. Loss of imprinting, which activates the normally silent maternal allele, has been implicated as an epigenetic marker for the enhanced risk of human cancer. However, many HCCs that display elevated IGF2 expression levels retain a normal imprinting pattern. Therefore, additional gene regulation mechanisms must also influence IGF2 expression in HCC. Hypothesis: Long-range genomic interactions are important for the regulation of IGF2 gene expression, and alterations in these long-range interactions lead to elevated IGF2 gene expression in HCC. To address this hypothesis I have utilized chromosome conformation capture carbon copy (5C) technology to elucidate long-range interactions involving the IGF2 promoters in a normal hepatocyte cell line, THLE-2, and an HCC cell line HepG2

Single electron yields from semileptonic charm and bottom hadron decays in Au plus Au collisions at root s(NN)=200 GeV

The PHENIX Collaboration at the Relativistic Heavy Ion Collider has measured open heavy flavor production in minimum bias Au + Au collisions at root s(NN) = 200 GeV via the yields of electrons from semileptonic decays of charm and bottom hadrons. Previous heavy flavor electron measurements indicated substantial modification in the momentum distribution of the parent heavy quarks owing to the quark-gluon plasma created in these collisions. For the first time, using the PHENIX silicon vertex detector to measure precision displaced tracking, the relative contributions from charm and bottom hadrons to these electrons as a function of transverse momentum are measured in Au + Au collisions. We compare the fraction of electrons from bottom hadrons to previously published results extracted from electron-hadron correlations in p + p collisions at root s(NN) = 200 GeV and find the fractions to be similar within the large uncertainties on both measurements for p(T) \u3e 4 GeV/c. We use the bottom electron fractions in Au + Au and p + p along with the previously measured heavy flavor electron R-AA to calculate the R-AA for electrons from charm and bottom hadron decays separately. We find that electrons from bottom hadron decays are less suppressed than those from charm for the region 3 \u3c p(T) \u3c 4 GeV/c

Measurement of parity-violating spin asymmetries in W-+/- production at midrapidity in longitudinally polarized p plus p collisions

We present midrapidity measurements from the PHENIX experiment of large parity-violating single-spin asymmetries of high transverse momentum electrons and positrons from W-+/-/Z decays, produced in longitudinally polarized p + p collisions at center of mass energies of root s = 500 and 510 GeV. These asymmetries allow direct access to the antiquark polarized parton distribution functions due to the parity-violating nature of the W-boson coupling to quarks and antiquarks. The results presented are based on data collected in 2011, 2012, and 2013 with an integrated luminosity of 240 pb(-1), which exceeds previous PHENIX published results by a factor of more than 27. These high Q(2) data probe the parton structure of the proton at W mass scale and provide an important addition to our understanding of the antiquark parton helicity distribution functions at an intermediate Bjorken x value of roughly M-W / root s = 0.16

Le FORUM, Vol. 39 No. 4

https://digitalcommons.library.umaine.edu/francoamericain_forum/1047/thumbnail.jp

Transverse energy production and charged-particle multiplicity at midrapidity in various systems from root s(NN)=7.7 to 200 GeV

Measurements of midrapidity charged-particle multiplicity distributions, dN(ch)/d eta, and midrapidity transverse-energy distributions, dE(T)/d eta, are presented for a variety of collision systems and energies. Included are distributions for Au + Au collisions at root s(NN) = 200, 130, 62.4, 39, 27, 19.6, 14.5, and 7.7 GeV, Cu + Cu collisions at root s(NN) = 200 and 62.4 GeV, Cu + Au collisions at root s(NN) = 200 GeV, U + U collisions at root s(NN) = 193 GeV, d + Au collisions at root s(NN) = 200 GeV, He-3 + Au collisions at root s(NN) = 200 GeV, and p + p collisions at root s(NN) = 200 GeV. Centrality-dependent distributions at midrapidity are presented in terms of the number of nucleon participants, N-part, and the number of constituent quark participants, N-qp. For all A + A collisions down to root s(NN) = 7.7 GeV, it is observed that the midrapidity data are better described by scaling with N-qp than scaling with N-part. Also presented are estimates of the Bjorken energy density, epsilon(BJ), and the ratio of dE(T)/d eta to dN(ch)/d eta, the latter of which is seen to be constant as a function of centrality for all systems

5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells

YesMammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene-rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and enhancers at the multi-TAD EDC locus in skin epithelial cells are cell type-specific and involve extensive contacts within TADs as well as between different gene-rich TADs, forming the framework for lineage-specific transcription.This study was supported by the grants 5R01AR064580 and 1RO1AR071727 to VAB, TKS and AAS, as well as by the grants from MRC (MR/ M010015/1) and BBSRC (BB/K010050/1) to VAB

The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance

The James Webb Space Telescope (JWST) is a large, infrared space telescope that has recently started its science program which will enable breakthroughs in astrophysics and planetary science. Notably, JWST will provide the very first observations of the earliest luminous objects in the Universe and start a new era of exoplanet atmospheric characterization. This transformative science is enabled by a 6.6 m telescope that is passively cooled with a 5-layer sunshield. The primary mirror is comprised of 18 controllable, low areal density hexagonal segments, that were aligned and phased relative to each other in orbit using innovative image-based wavefront sensing and control algorithms. This revolutionary telescope took more than two decades to develop with a widely distributed team across engineering disciplines. We present an overview of the telescope requirements, architecture, development, superb on-orbit performance, and lessons learned. JWST successfully demonstrates a segmented aperture space telescope and establishes a path to building even larger space telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25 figure

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

5C looping interactions at the EDC locus involve gene promoters and enhancers in keratinocytes.

<p><b>(a)</b> Vent diagram indicating the overlap of the significant 5C interactions (q<0.05) between the 5C library replicates and pie chart showing the number of all “true” intra-TAD (red) and inter-TAD (green) 5C interactions in KCs. <b>(b)</b> Pie-chart indicating number of 5C interactions connecting two regions anchoring transcription start sites (TSSs) within 5kb (promoter-promoter interactions); one contacting region anchoring a TSS within 5kb and the other contacting region not anchoring a TSS within 5 kb (promoter-non promoter interactions); and both contacting regions not anchoring TSSs within 5kb (non-promoter–non promoter interactions). <b>(c)</b> Genome browser images of the normalized ChIP-seq signals for H3K4me1 and H3K27ac enrichment as well as the position of the putative gene enhancers at the EDC containing locus in KCs aligned to the schematic locus map. Genome browser images of the normalized ChIP-seq signals for several enhancer regions at small scale are provided as examples. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006966#sec010" target="_blank">Materials and Methods</a> section for details of ChIP-seq peak calling and pursing the putative enhancers. The TAD border midpoints are indicated by the green lines.</p