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Innate defenses against retroelements

English title Innate defenses against retroelements
Applicant Trono Didier
Number 135713
Funding scheme Project funding
Research institution Laboratoire de virologie et génétique FSV-GHI EPFL
Institution of higher education EPF Lausanne - EPFL
Main discipline Molecular Biology
Start/End 01.04.2011 - 31.03.2014
Approved amount 930'000.00
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Keywords (9)

HIV; endogenous retroelements; epigenetics; CMV; latency; KRAB-ZFP; KAP1; AIDS; cancer

Lay Summary (English)

Lead
Lay summary

Retroelements are genetic invaders that include human pathogens such as the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV), as well as so-called endogenous retroviruses and retrotransposons. The latter are mobile genetic elements that are very abundant in the genomes of higher organisms, for which they represent important driving forces of evolution. Sophisticated regulatory processes are at play to prevent the uncontrolled spread of endogenous retroelements and infections by their exogenous counterparts such as HIV. We recently revealed that, amongst these, the so-called KRAB/KAP system plays a prominent role. The present project aims at pursuing our molecular exploration of these all-important innate defense mechanisms.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation
Singh Kulwant, CassanoMarco, Planet Evarist, Sebastian Soji, Jang Suk Min, Sohi Gurjeev, Faralli Hervé, Choi Jinmi, YounHong-Duk, Dilworth Jeffrey, Trono Didier (2015), A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation, in Genes&development, 29(5), 513-525.
Drawing a fine line on endogenous retroelement activity
Castro-Diaz Nathaly, Friedli Marc, Trono Didier (2015), Drawing a fine line on endogenous retroelement activity, in Mobile genetic elements, 5(1), 1-6.
Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch
Rauwel Benjamin, Jang Suk Min, Cassano Marco, Kapopoulou Adamandia, Barde Isabelle, Trono Didier (2015), Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch, in eLife, 4, 1-20.
The Developmental Control of Transposable Elements and the Evolution of Higher Species
Friedli Marc, Trono Didier (2015), The Developmental Control of Transposable Elements and the Evolution of Higher Species, in Annual Review of Cell and Developmental Biology, 429-451.
TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells
Fasching Liana, Kapopoulou Adamandia, Sachdeva Rohit, Petri Rebecca, Jönsson Marie, Männe Christian, Turelli Priscilla, Jern Patrick, Cammas Florence, Trono Didier, Jakobsson Johan (2015), TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells, in Cell Reports, 10(1), 20-28.
[A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy].
Barde Isabelle, Rauwel Benjamin, Marin-Florez Ray Marcel, Corsinotti Andrea, Laurenti Elisa, VerpSonia, Offner Sandra, Marquis Julien, KapopoulouAdamandia, VanicekJiri, Trono Didier (2014), [A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy]., in M S-Medecine Sciences, 30(1), 12-15.
As Time Goes by: KRABs Evolve to KAP Endogenous Retroelements
Imbeault Michael, Trono Didier (2014), As Time Goes by: KRABs Evolve to KAP Endogenous Retroelements, in Developmental Cell, 31(3), 257-258.
Evolutionally dynamic L1 regulation in embryonic stem cells
Castro-Diaz Nathaly, Ecco Gabriela, Coluccio Andrea, Kapopoulou Adamandia, Yazdanpanah Benyamin, Friedli Marc, Duc Julien, Jang Suk Min, Turelli Priscilla, Trono Didier (2014), Evolutionally dynamic L1 regulation in embryonic stem cells, in Gene&Development, 28(13), 1397-1409.
Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network
Gubelmann Carine, Schwalie Petra, Raghav Sunil, Roeder Eva, Delessa Tenagne, Kiehlmann Elke, Waszak Sebastian, Corsinotti Andrea, Udin Gilles, Holcombe Wiebke, Rudofsky Gottfried, Trono Didier, WolfrumChristian, Deplancke Barte (2014), Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network, in Elife, 3, 03346.
Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements
Turelli Priscilla, Castro-Diaz Nathaly, Marzetta Flavia, Kapopoulou Adamandia, Raclot Charlène, Duc Julien, Thieng Vannary, Quenneville Simon, Trono Didier (2014), Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements, in Genome Research, 24(8), 1260-1270.
Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency
FriedliMarc, Turelli Priscilla, Kapopoulou Adamandia, Rauwel Benjamin, Castro-Diaz Nathaly, Rowe Helen, Ecco Gabriela, Unzu Carmen, Planet Evarist, LombardoAngelo, MangeatBastien, Wildhaber Barbara, NaldiniLuigi, TronoDidier (2014), Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency, in Genome Research, 24(8), 1251-1259.
A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.
Barde Isabelle, Rauwel Benjamin, Marin-Florez Ray Marcel, Corsinotti Andrea, Laurenti Elisa, Verp Sonia, Offner Sandra, Marquis Julien, Kapopoulou Adamandia, Vanicek Jiri, Trono Didier (2013), A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy., in Science (New York, N.Y.), 340(6130), 350-3.
A switch between topological domains underlies HoxD genes collinearity in mouse limbs.
Andrey Guillaume, Montavon Thomas, Mascrez Bénédicte, Gonzalez Federico, Noordermeer Daan, Leleu Marion, Trono Didier, Spitz François, Duboule Denis (2013), A switch between topological domains underlies HoxD genes collinearity in mouse limbs., in Science (New York, N.Y.), 340(6137), 1234167-1234167.
De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET.
Rowe Helen M, Friedli Marc, Offner Sandra, Verp Sonia, Mesnard Daniel, Marquis Julien, Aktas Tugce, Trono Didier (2013), De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET., in Development (Cambridge, England), 140(3), 519-29.
Global and stage specific patterns of Krüppel-associated-box zinc finger protein gene expression in murine early embryonic cells.
Corsinotti Andrea, Kapopoulou Adamandia, Gubelmann Carine, Imbeault Michael, Santoni de Sio Francesca R, Rowe Helen M, Mouscaz Yoann, Deplancke Bart, Trono Didier (2013), Global and stage specific patterns of Krüppel-associated-box zinc finger protein gene expression in murine early embryonic cells., in PloS one, 8(2), 56721-56721.
Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression.
Márquez C, Poirier G L, Cordero M I, Larsen M H, Groner A, Marquis J, Magistretti P J, Trono D, Sandi C (2013), Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression., in Translational psychiatry, 3, 216-216.
TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells.
Rowe Helen M, Kapopoulou Adamandia, Corsinotti Andrea, Fasching Liana, Macfarlan Todd S, Tarabay Yara, Viville Stéphane, Jakobsson Johan, Pfaff Samuel L, Trono Didier (2013), TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells., in Genome research, 23(3), 452-61.
A novel lentiviral vector targets gene transfer into human hematopoietic stem cells in marrow from patients with bone marrow failure syndrome and in vivo in humanized mice.
Frecha Cecilia, Costa Caroline, Nègre Didier, Amirache Fouzia, Trono Didier, Rio Paula, Bueren Juan, Cosset François-Loïc, Verhoeyen Els (2012), A novel lentiviral vector targets gene transfer into human hematopoietic stem cells in marrow from patients with bone marrow failure syndrome and in vivo in humanized mice., in Blood, 119(5), 1139-50.
Gene therapy: too much splice can spoil the dish.
Trono Didier (2012), Gene therapy: too much splice can spoil the dish., in The Journal of clinical investigation, 122(5), 1600-2.
KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function.
Santoni de Sio Francesca R, Massacand Joanna, Barde Isabelle, Offner Sandra, Corsinotti Andrea, Kapopoulou Adamandia, Bojkowska Karolina, Dagklis Antonis, Fernandez Marylise, Ghia Paolo, Thomas James H, Pinschewer Daniel, Harris Nicola, Trono Didier (2012), KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function., in Blood, 119(20), 4675-85.
KAP1 regulates gene networks controlling T-cell development and responsiveness.
Santoni de Sio Francesca R, Barde Isabelle, Offner Sandra, Kapopoulou Adamandia, Corsinotti Andrea, Bojkowska Karolina, Genolet Raphaël, Thomas James H, Luescher Immanuel F, Pinschewer Daniel, Harris Nicola, Trono Didier (2012), KAP1 regulates gene networks controlling T-cell development and responsiveness., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 26(11), 4561-75.
The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation.
White David, Rafalska-Metcalf Ilona U, Ivanov Alexey V, Corsinotti Andrea, Peng Hongzhuang, Lee Sheng-Chung, Trono Didier, Janicki Susan M, Rauscher Frank J (2012), The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation., in Molecular cancer research : MCR, 10(3), 401-14.
The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development.
Quenneville Simon, Turelli Priscilla, Bojkowska Karolina, Raclot Charlène, Offner Sandra, Kapopoulou Adamandia, Trono Didier (2012), The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development., in Cell reports, 2(4), 766-73.
The Kruppel-associated box repressor domain can induce reversible heterochromatization of a mouse locus in vivo.
Groner Anna C, Tschopp Patrick, Challet Ludivine, Dietrich Jens-Erik, Verp Sonia, Offner Sandra, Barde Isabelle, Rodriguez Ivan, Hiiragi Takashi, Trono Didier (2012), The Kruppel-associated box repressor domain can induce reversible heterochromatization of a mouse locus in vivo., in The Journal of biological chemistry, 1-15.
A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing.
Meylan Sylvain, Groner Anna C, Ambrosini Giovanna, Malani Nirav, Quenneville Simon, Zangger Nadine, Kapopoulou Adamandia, Kauzlaric Annamaria, Rougemont Jacques, Ciuffi Angela, Bushman Frederic D, Bucher Philipp, Trono Didier (2011), A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing., in BMC genomics, 12, 378-378.
Chromosome conformation capture uncovers potential genome-wide interactions between human conserved non-coding sequences.
Robyr Daniel, Friedli Marc, Gehrig Corinne, Arcangeli Mélanie, Marin Marilyn, Guipponi Michel, Farinelli Laurent, Barde Isabelle, Verp Sonia, Trono Didier, Antonarakis Stylianos E (2011), Chromosome conformation capture uncovers potential genome-wide interactions between human conserved non-coding sequences., in PloS one, 6(3), 17634-17634.
Genomic instability in induced stem cells.
Pasi C E, Dereli-Öz A, Negrini S, Friedli M, Fragola G, Lombardo A, Van Houwe G, Naldini L, Casola S, Testa G, Trono D, Pelicci P G, Halazonetis T D (2011), Genomic instability in induced stem cells., in Cell death and differentiation, 18(5), 745-53.
In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions.
Quenneville Simon, Verde Gaetano, Corsinotti Andrea, Kapopoulou Adamandia, Jakobsson Johan, Offner Sandra, Baglivo Ilaria, Pedone Paolo V, Grimaldi Giovanna, Riccio Andrea, Trono Didier (2011), In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions., in Molecular cell, 44(3), 361-72.
Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease.
Barde I, Laurenti E, Verp S, Wiznerowicz M, Offner S, Viornery A, Galy A, Trumpp A, Trono D (2011), Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease., in Gene therapy, 18(11), 1087-97.
Measuring in vivo protein half-life.
Bojkowska Karolina, Santoni de Sio Francesca, Barde Isabelle, Offner Sandra, Verp Sonia, Heinis Christian, Johnsson Kai, Trono Didier (2011), Measuring in vivo protein half-life., in Chemistry & biology, 18(6), 805-15.

Associated projects

Number Title Start Funding scheme
150831 A Chromatin Sharing Instrument for Analyses of Gene Regulation and Chromatin Structure 01.12.2013 R'EQUIP
120035 Innate defenses against retroelements 01.04.2008 Project funding
128157 KRAB/KAP1 epigenetic regulation and pluripotent stem cell homeostasis 01.03.2010 NRP 63 Stem cells and regenerative medicine
133797 Biology Needs Ultra High Throughput DNA Sequencing 01.06.2011 R'EQUIP
152879 KRAB/KAP and the control of transposable elements 01.04.2014 Project funding
122691 KRAB/KAP1 epigenetic regulation in the control of memory and emotional traits: from mice to humans. 01.12.2008 Sinergia

Abstract

Retroelements constitute important evolutionary forces for the genome of higher organisms, yet their uncontrolled spread, whether from endogenous loci or within the context of viral infections, can cause diseases such as cancer, hepatitis and AIDS. Correspondingly, this process is limited by a variety of host-encoded activities, amongst which epigenetics plays a role of increasingly recognized importance. Our recent work has revealed that KRAB/KAP1-mediated transcriptional repression is crucial to the silencing of endogenous retroviruses during early embryogenesis. Under the auspices of the present “Bonus of Excellence” award, we will follow up on this discovery and more broadly study the impact of epigenetic regulation on the control of viral and virus-related genetic invaders. The objectives of this three-year funding period will be to:1.Dissect further the mechanism of KRAB/KAP1-mediated control of endogenous retroviruses.2.Probe a potential implication of this regulation system in the establishment and maintenance of HIV latency.3.Explore the modalities of epigenetic control of non-LTR retrotransposons.4.Investigate a putative role for KRAB/KAP1 in CMV latency and reactivation.
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