title: Trim24-repressed VL30 retrotransposons regulate gene expression by producing noncoding RNA.
abstract: Trim24 (Tif1α) and Trim33 (Tif1γ) interact to form a co-repressor complex that suppresses murine hepatocellular carcinoma. Here we show that Trim24 and Trim33 cooperatively repress retinoic acid receptor-dependent activity of VL30-class endogenous retroviruses (ERVs) in liver. In Trim24-knockout hepatocytes, VL30 derepression leads to accumulation of reverse-transcribed VL30 cDNA in the cytoplasm that correlates with activation of the viral-defense interferon responses mimicking the preneoplastic inflammatory state seen in human liver following exogenous viral infection. Furthermore, upon derepression, VL30 long terminal repeats (LTRs) act as promoter and enhancer elements deregulating expression of neighboring genes and generating enhancer RNAs that are required for LTR enhancer activity in hepatocytes in vivo. These data reinforce the role of the TRIM family of proteins in retroviral restriction and antiviral defense and provide an example of an ERV-derived oncogenic regulatory network.
authors: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
authors: Benjamin
authors: B
authors: Herquel
authors: Khalid
authors: K
authors: Ouararhni
authors: Igor
authors: I
authors: Martianov
authors: Stéphanie
authors: S
authors: Le Gras
authors: Tao
authors: T
authors: Ye
authors: Céline
authors: C
authors: Keime
authors: Thierry
authors: T
authors: Lerouge
authors: Bernard
authors: B
authors: Jost
authors: Florence
authors: F
authors: Cammas
authors: Régine
authors: R
authors: Losson
authors: Irwin
authors: I
authors: Davidson
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D008113:Liver Neoplasms / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D022661:RNA, Untranslated; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics*; D020079:Terminal Repeat Sequences; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C489323:Mbd1 protein, mouse; D009687:Nuclear Proteins; D022661:RNA, Untranslated; D018168:Receptors, Retinoic Acid; D018626:Retroelements; D014157:Transcription Factors; C491420:Trim33 protein, mouse; C093517:transcriptional intermediary factor 1
references: Cell Cycle. 2008 Dec;7(23):3647-52
references: 19029830
references: Nature. 2010 Dec 16;468(7326):927-32
references: 21164480
references: Nat Biotechnol. 2010 May;28(5):511-5
references: 20436464
references: Cell. 2010 Oct 1;143(1):46-58
references: 20887892
references: Cell Death Differ. 2012 Feb;19(2):220-31
references: 21701496
references: Recent Results Cancer Res. 2011;185:135-48
references: 21822824
references: Biochem Biophys Res Commun. 1994 Aug 30;203(1):545-52
references: 8074702
references: PLoS Biol. 2010 May 11;8(5):e1000384
references: 20485488
references: Mol Cell. 2011 Jul 8;43(1):85-96
references: 21726812
references: Bioinformatics. 2009 May 1;25(9):1105-11
references: 19289445
references: Nat Genet. 2007 Dec;39(12):1500-6
references: 18026104
references: Nature. 2010 Jan 14;463(7278):237-40
references: 20075919
references: Nat Rev Microbiol. 2005 Oct;3(10):799-808
references: 16175175
references: Cell. 2008 Aug 22;134(4):587-98
references: 18724932
references: Nucleic Acids Res. 2012 Feb;40(4):1446-59
references: 22013162
references: Transcription. 2011 Sep-Oct;2(5):231-6
references: 22231120
references: Cell. 2011 Feb 4;144(3):327-39
references: 21295696
references: Curr Opin Immunol. 2011 Feb;23(1):46-56
references: 21131187
references: Nucleic Acids Res. 2011 Mar;39(6):e35
references: 21177645
references: EMBO J. 1999 Nov 15;18(22):6385-95
references: 10562550
references: Hum Mol Genet. 2009 Oct 15;18(R2):R130-6
references: 19808788
references: Cell. 2008 Aug 22;134(4):569-71
references: 18724930
references: Nat Genet. 2006 Aug;38(8):917-20
references: 16845398
references: J Biol Chem. 2011 Sep 23;286(38):33369-79
references: 21768647
references: Mol Cell. 2006 Aug 4;23(3):365-75
references: 16885026
references: Mol Cell. 2012 Feb 24;45(4):447-58
references: 22264824
references: Genome Biol. 2010;11(10):R106
references: 20979621
references: Nat Rev Genet. 2012 Mar 16;13(4):283-96
references: 22421730
references: Biochim Biophys Acta. 1997 May 2;1352(1):33-47
references: 9177481
references: J Biol Chem. 1993 Feb 15;268(5):3251-9
references: 7679109
references: EMBO Mol Med. 2011 Sep;3(9):513-27
references: 21826793
references: Curr Opin Genet Dev. 2011 Apr;21(2):194-8
references: 21330130
references: Nat Genet. 2011 Sep 25;43(11):1154-9
references: 21946353
references: Nat Genet. 2010 Jul;42(7):631-4
references: 20526341
references: Nature. 2010 May 13;465(7295):182-7
references: 20393465
references: J Virol. 1994 Jan;68(1):276-88
references: 8254739
references: Nat Genet. 2006 Aug;38(8):910-6
references: 16845400
references: PLoS Genet. 2010 Apr 29;6(4):e1000927
references: 20442873
references: Nature. 2009 Apr 30;458(7242):1201-4
references: 19270682
references: Nat Struct Mol Biol. 2011 Jul 17;18(8):956-63
references: 21765417
references: Nat Rev Cancer. 2011 Oct 07;11(11):792-804
references: 21979307
references: J Hepatol. 2012 Mar;56(3):704-13
references: 22120206
references: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8212-7
references: 21531907