title: Reprogramming of the HepG2 genome by long interspersed nuclear element-1.
abstract: Long Interspersed Nuclear Element-1 (LINE-1 or L1) is an autonomous, mobile element within the human genome that transposes via a "copy and paste" mechanism and relies upon L1-encoded endonuclease and reverse transcriptase (RT) activities to compromise genome integrity. L1 has been implicated in various forms of cancer, but its role in the regulation of the oncogenic phenotype is not understood. The present studies were conducted to evaluate mechanisms of genetic regulatory control in HepG2 cells by human L1, or a D702Y mutant deficient in RT activity, and their influence on cellular phenotype. Forced expression of synthetic L1 ORF1p and ORF2p was associated with formation of cytoplasmic foci and minor association with the nuclear compartment. While de novo L1 mobilizations were only identified in cells expressing wild type L1, and were absent in the D702Y mutant, changes in gene expression profiles involved RT dependent as well as RT independent mechanisms. Synthetic L1 altered the expression of 24 in silico predicted genetic targets; ten of which showed RT-dependence, ten RT-independence, and four reciprocal regulatory control by both wild type and RT mutant. Of five targets examined, only VCAM1 and PTPRB colocalized with newly retrotransposed wild type L1. Biological discretization to partition patterns of gene expression into unique frequencies identified adhesion, inflammation, and cellular metabolism as key processes targeted for molecular interference with disruption of epithelial-to-mesenchymal programming seen irrespective of the RT phenotype. These findings establish L1 as a key regulator of genome plasticity and EMT via mechanisms independent of RT activity.
authors: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
authors: Pasano
authors: P
authors: Bojang
authors: Ruth A
authors: RA
authors: Roberts
authors: Mark J
authors: MJ
authors: Anderton
authors: Kenneth S
authors: KS
authors: Ramos
mesh_terms: D019084:Fluorescent Antibody Technique, Indirect; D056945:Hep G2 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D018626:Retroelements / Q000235:genetics*
chemical_list: D018626:Retroelements
keywords: Epithelial-to-mesenchymal transition; Genetic reprogramming; Long interspersed nuclear element-1; Retrotransposons; Reverse transcriptase
references: Epidemiology. 2010 Nov;21(6):819-28
references: 20805753
references: Nat Rev Genet. 2011 Aug 18;12(9):615-27
references: 21850042
references: Biochem Biophys Res Commun. 1998 Dec 30;253(3):566-70
references: 9918768
references: Cell. 1996 Nov 29;87(5):905-16
references: 8945517
references: Annu Rev Genomics Hum Genet. 2011;12:187-215
references: 21801021
references: Mol Cell Biol. 2007 Sep;27(18):6469-83
references: 17562864
references: Mol Cell Biol. 1990 Dec;10(12):6718-29
references: 1701022
references: Cell. 2007 Mar 23;128(6):1089-103
references: 17346786
references: Cell. 1988 May 6;53(3):391-400
references: 3365767
references: Cell. 2006 Feb 24;124(4):783-801
references: 16497588
references: Cancer Res. 2006 Mar 1;66(5):2616-20
references: 16510580
references: Science. 1991 Dec 20;254(5039):1808-10
references: 1722352
references: Genes Dev. 1991 Apr;5(4):521-32
references: 1849106
references: Dev Cell. 2007 Apr;12(4):503-14
references: 17395546
references: Birth Defects Res A Clin Mol Teratol. 2011 Aug;91(8):693-702
references: 21384534
references: J Biol Chem. 2003 Jul 25;278(30):28201-9
references: 12714586
references: Hum Mol Genet. 2004 May 15;13(10):1041-8
references: 15028673
references: Mutat Res. 2009 Jun 1;665(1-2):20-8
references: 19427507
references: Cell. 1996 Nov 29;87(5):917-27
references: 8945518
references: Genes Cells. 2007 Oct;12(10):1101-10
references: 17903170
references: Cell. 2008 Oct 3;135(1):23-35
references: 18854152
references: Mol Oncol. 2013 Aug;7(4):812-25
references: 23648019
references: Genes Dev. 1992 Aug;6(8):1457-65
references: 1379564
references: Nat Genet. 2001 May;28(1):77-81
references: 11326281
references: Science. 1991 Dec 20;254(5039):1805-8
references: 1662412
references: Science. 1996 Oct 25;274(5287):536-9
references: 8928008
references: Int J Hematol. 2006 Apr;83(3):213-6
references: 16720550
references: RNA Biol. 2010 Nov-Dec;7(6):706-11
references: 21045547
references: Mol Cell Biol. 2001 Mar;21(6):1973-85
references: 11238933
references: Toxicol Sci. 2010 May;115(1):66-79
references: 20106945
references: EMBO J. 1990 May;9(5):1529-34
references: 1691708
references: Int Rev Cytol. 1999;186:1-48
references: 9770296
references: J Biol Chem. 1993 Feb 15;268(5):3251-9
references: 7679109
references: Epigenetics. 2011 Mar;6(3):355-67
references: 21150308
references: Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10155-60
references: 9294179
references: EMBO J. 1996 Feb 1;15(3):630-9
references: 8599946
references: Cell. 2007 Apr 6;129(1):69-82
references: 17418787
references: Oncogene. 2005 Jun 2;24(24):3923-31
references: 15806170
references: Curr Mol Med. 2010 Jul;10(5):511-21
references: 20540701
references: Nature. 2001 Feb 15;409(6822):860-921
references: 11237011
references: J Gene Med. 2004 Apr;6(4):395-404
references: 15079814
references: Gene. 1997 Apr 21;189(2):227-34
references: 9168132
references: Science. 1984 Nov 16;226(4676):792-801
references: 15739260
references: Genomics. 2007 Aug;90(2):176-85
references: 17521869
references: Genomics. 2000 Jul 15;67(2):201-9
references: 10903845
references: Science. 2012 Aug 24;337(6097):967-71
references: 22745252
references: Nucleic Acids Res. 2003 Aug 15;31(16):4929-40
references: 12907736
references: FEBS Lett. 2006 Jan 23;580(2):661-8
references: 16412437