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      Retroviral DNA Integration: ASLV, HIV, and MLV Show Distinct Target Site Preferences

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          Abstract

          The completion of the human genome sequence has made possible genome-wide studies of retroviral DNA integration. Here we report an analysis of 3,127 integration site sequences from human cells. We compared retroviral vectors derived from human immunodeficiency virus (HIV), avian sarcoma-leukosis virus (ASLV), and murine leukemia virus (MLV). Effects of gene activity on integration targeting were assessed by transcriptional profiling of infected cells. Integration by HIV vectors, analyzed in two primary cell types and several cell lines, strongly favored active genes. An analysis of the effects of tissue-specific transcription showed that it resulted in tissue-specific integration targeting by HIV, though the effect was quantitatively modest. Chromosomal regions rich in expressed genes were favored for HIV integration, but these regions were found to be interleaved with unfavorable regions at CpG islands. MLV vectors showed a strong bias in favor of integration near transcription start sites, as reported previously. ASLV vectors showed only a weak preference for active genes and no preference for transcription start regions. Thus, each of the three retroviruses studied showed unique integration site preferences, suggesting that virus-specific binding of integration complexes to chromatin features likely guides site selection.

          Abstract

          Retroviruses have potential for gene therapy only if they do not activate endogenous genes. Of three tested retroviral vectors, ASLV showed no preference for integration into human transcription start regions

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          Most cited references32

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          In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.

          A retroviral vector system based on the human immunodeficiency virus (HIV) was developed that, in contrast to a murine leukemia virus-based counterpart, transduced heterologous sequences into HeLa cells and rat fibroblasts blocked in the cell cycle, as well as into human primary macrophages. Additionally, the HIV vector could mediate stable in vivo gene transfer into terminally differentiated neurons. The ability of HIV-based viral vectors to deliver genes in vivo into nondividing cells could increase the applicability of retroviral vectors in human gene therapy.
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            Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs.

            Using high-density oligonucleotide arrays representing essentially all nonrepetitive sequences on human chromosomes 21 and 22, we map the binding sites in vivo for three DNA binding transcription factors, Sp1, cMyc, and p53, in an unbiased manner. This mapping reveals an unexpectedly large number of transcription factor binding site (TFBS) regions, with a minimal estimate of 12,000 for Sp1, 25,000 for cMyc, and 1600 for p53 when extrapolated to the full genome. Only 22% of these TFBS regions are located at the 5' termini of protein-coding genes while 36% lie within or immediately 3' to well-characterized genes and are significantly correlated with noncoding RNAs. A significant number of these noncoding RNAs are regulated in response to retinoic acid, and overlapping pairs of protein-coding and noncoding RNAs are often coregulated. Thus, the human genome contains roughly comparable numbers of protein-coding and noncoding genes that are bound by common transcription factors and regulated by common environmental signals.
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              The human transcriptome map: clustering of highly expressed genes in chromosomal domains.

              The chromosomal position of human genes is rapidly being established. We integrated these mapping data with genome-wide messenger RNA expression profiles as provided by SAGE (serial analysis of gene expression). Over 2.45 million SAGE transcript tags, including 160,000 tags of neuroblastomas, are presently known for 12 tissue types. We developed algorithms to assign these tags to UniGene clusters and their chromosomal position. The resulting Human Transcriptome Map generates gene expression profiles for any chromosomal region in 12 normal and pathologic tissue types. The map reveals a clustering of highly expressed genes to specific chromosomal regions. It provides a tool to search for genes that are overexpressed or silenced in cancer.
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                Author and article information

                Journal
                PLoS Biol
                pbio
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                August 2004
                17 August 2004
                : 2
                : 8
                : e234
                Affiliations
                [1] 1Department of Microbiology, University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, United States of America
                [2] 2Gen-Probe, San Diego California, United States of America
                [3] 3Genomic Analysis Laboratory, The Salk Institute La Jolla, California, United States of America
                [4] 4Department of Family/Preventive Medicine, University of California at San Diego School of Medicine San Diego, CaliforniaUnited States of America
                Article
                10.1371/journal.pbio.0020234
                509299
                15314653
                c9de1958-59b8-48d0-9e8a-9f121d0215f4
                Copyright: © 2004 Mitchell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
                History
                : 20 February 2004
                : 24 May 2004
                Categories
                Research Article
                Genetics/Genomics/Gene Therapy
                Virology
                Viruses
                Homo (Human)

                Life sciences
                Life sciences

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