Project

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KRAB/KAP1 epigenetic regulation in the control of memory and emotional traits: from mice to humans.

English title KRAB/KAP1 epigenetic regulation in the control of memory and emotional traits: from mice to humans.
Applicant Trono Didier
Number 122691
Funding scheme Sinergia
Research institution Laboratoire de virologie et génétique FSV-GHI EPFL
Institution of higher education EPF Lausanne - EPFL
Main discipline Genetics
Start/End 01.12.2008 - 30.11.2011
Approved amount 3'234'118.00
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All Disciplines (3)

Discipline
Genetics
Molecular Biology
Neurophysiology and Brain Research

Keywords (10)

Epigenetics; KRAB; KAP1; KRAB-ZFP; memory; behavior; stress; depression; polymorphism; hippocampus

Lay Summary (English)

Lead
Lay summary
This project aims at exploring the genetic bases of vulnerability to behavioral stress and stress-related disorders such as hyperanxiety, post-traumatic stress syndrome and depression. The four groups engaged in tackling this objective will capitalize on their recent discovery that a particular family of so-called epigenetic regulators of gene expression conditions susceptibility to behavioral stress and stress-induced cognitive defects in the mouse, and on their previous development of techniques to identify genetic factors related to emotional and non-emotional memory in humans. The study will combine molecular, genetic, behavioral and neuroimaging appraoches in a truly multidisciplinary atmosphere. The definition of genetic predictors of stress-induced pathologies will help design new approaches for the prevention and treatment of these pandemic diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
A genome-wide survey of human short-term memory
Papassotiropoulos A, Henke K, Stefanova E, Aerni A, Muller A, Demougin P, Vogler C, Sigmund JC, Gschwind L, Huynh KD, Coluccia D, Mondadori CR, Hanggi J, Buchmann A, Kostic V, Novakovic I, van den Bussche H, Kaduszkiewicz H, Weyerer S, Bickel H, Riedel-Heller S, Pentzek M, Wiese B, Dichgans M, Wagner M (2011), A genome-wide survey of human short-term memory, in MOLECULAR PSYCHIATRY, 16(2), 184-192.
A peptide mimetic targeting trans-homophilic NCAM binding sites promotes spatial learning and neural plasticity in the hippocampus.
Kraev Igor, Henneberger Christian, Rossetti Clara, Conboy Lisa, Kohler Lene B, Fantin Martina, Jennings Alistair, Venero Cesar, Popov Victor, Rusakov Dmitri, Stewart Michael G, Bock Elisabeth, Berezin Vladimir, Sandi Carmen (2011), A peptide mimetic targeting trans-homophilic NCAM binding sites promotes spatial learning and neural plasticity in the hippocampus., in PloS one, 6(8), 23433-23433.
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.
Dynamic control of endogenous retroviruses during development.
Rowe Helen M, Trono Didier (2011), Dynamic control of endogenous retroviruses during development., in Virology, 411(2), 273-87.
Evidence for a role of oxytocin receptors in the long-term establishment of dominance hierarchies.
Timmer Marjan, Cordero M Isabel, Sevelinges Yannick, Sandi Carmen (2011), Evidence for a role of oxytocin receptors in the long-term establishment of dominance hierarchies., in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36(11), 2349-56.
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.
Glucocorticoids act on glutamatergic pathways to affect memory processes.
Sandi Carmen (2011), Glucocorticoids act on glutamatergic pathways to affect memory processes., in Trends in neurosciences, 34(4), 165-76.
Homology-based identification of capsid determinants that protect HIV1 from human TRIM5α restriction.
Maillard Pierre V, Zoete Vincent, Michielin Olivier, Trono Didier (2011), Homology-based identification of capsid determinants that protect HIV1 from human TRIM5α restriction., in The Journal of biological chemistry, 286(10), 8128-40.
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.
Profaning the ultimate sanctuary: HIV latency in hematopoietic stem cells.
Trono Didier, Marzetta Flavia (2011), Profaning the ultimate sanctuary: HIV latency in hematopoietic stem cells., in Cell host & microbe, 9(3), 170-2.
Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory.
Heck Angela, Vogler Christian, Gschwind Leo, Ackermann Sandra, Auschra Bianca, Spalek Klara, Rasch Björn, de Quervain Dominique, Papassotiropoulos Andreas (2011), Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory., in PloS one, 6(12), 29337-29337.
Stress during Adolescence Increases Novelty Seeking and Risk-Taking Behavior in Male and Female Rats.
Toledo-Rodriguez Maria, Sandi Carmen (2011), Stress during Adolescence Increases Novelty Seeking and Risk-Taking Behavior in Male and Female Rats., in Frontiers in behavioral neuroscience, 5, 17-17.
Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities.
Bulliard Yannick, Narvaiza Iñigo, Bertero Alessandro, Peddi Shyam, Röhrig Ute F, Ortiz Millán, Zoete Vincent, Castro-Díaz Nataly, Turelli Priscilla, Telenti Amalio, Michielin Olivier, Weitzman Matthew D, Trono Didier (2011), Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities., in Journal of virology, 85(4), 1765-76.
Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations.
Bisaz Reto, Sandi Carmen (2011), Vulnerability of conditional NCAM-deficient mice to develop stress-induced behavioral alterations., in Stress (Amsterdam, Netherlands), 15(2), 195-206.
A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-related gene.
Papassotiropoulos A, Stefanova E, Vogler C, Gschwind L, Ackermann S, Spalek K, Rasch B, Heck A, Aerni A, Hanser E, Demougin P, Huynh K-D, Luechinger R, Klarhöfer M, Novakovic I, Kostic V, Boesiger P, Scheffler K, de Quervain D J-F, A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-related gene., in Molecular psychiatry.
Microarray-Based Maps of Copy-Number Variant Regions in European and Sub-Saharan Populations
Vogler C, Gschwind L, Rothlisberger B, Huber A, Filges I, Miny P, Auschra B, Stetak A, Demougin P, Vukojevic V, Kolassa IT, Elbert T, de Quervain DJF, Papassotiropoulos A, Microarray-Based Maps of Copy-Number Variant Regions in European and Sub-Saharan Populations, in PLOS ONE, 5(12).
Social memories in rodents: Methods, mechanisms and modulation by stress.
van der Kooij Michael A, Sandi Carmen, Social memories in rodents: Methods, mechanisms and modulation by stress., in Neuroscience and biobehavioral reviews.

Associated projects

Number Title Start Funding scheme
133797 Biology Needs Ultra High Throughput DNA Sequencing 01.06.2011 R'EQUIP
135713 Innate defenses against retroelements 01.04.2011 Project funding
135710 Stress and the Social Brain: The role of neuropeptides and synapse-specific neuroplasticity molecules 01.04.2011 Project funding
133853 A phenogenomic approach to identify novel determinants of mitochondrial function 01.10.2011 R'EQUIP

Abstract

JOINED RESEARCH SUMMARYThis proposal aims at exploring the molecular and genetic bases of vulnerability to behavioral stress and stress-related disorders, taking as a starting point the role of epigenetics in this process. The four participating groups have all recently contributed to this topic by i) discovering that transcriptional modulation by the KRAB/KAP1 epigenetic regulatory system in the hippocampus conditions vulnerability to behavioral stress and stress-induced cognitive defects in the mouse (DT & CS), and ii) identifying genetic factors related to non-emotional and emotional memory through behavioral and genetic studies in humans, including patients suffering from traumatic memories and post-traumatic stress disorder (DdQ & AP). The four groups will pool efforts to tackle this as yet largely unexplored problematic through a combination of molecular biology, mouse genetics, mouse and human behavioral neurobiology, human genetics and neuroimaging. The specific aims of this project are:1.To characterize molecularly the stress vulnerability of KAP1 KO mice by asking: a)Is the phenotype of KAP1 knockout mice restricted to a particular neuro-developmental stage? b)Is the increased stress vulnerability of KAP1 KO mice reversible?c)What KAP1 molecular determinants are essential for normal vulnerability to stress?d)What KRAB-ZFPs control KAP1-dependent vulnerability to behavioral stress?e)What are the downstream effectors of abnormal stress responses in KAP1 KO mice?f)Which are dysregulated at baseline and after stressful challenges?g)What are their roles in increasing stress vulnerability? How do they act?h)What is the mechanism of their epigenetic regulation and dysregulation in the absence of KAP1?2. To further the behavioral and neurobiological characterization of KAP1 KO mice, by:a)Expanding the behavioral characterization of KAP1 forebrain KO mice to obtain a precise picture of the emotional and cognitive consequences of this mutation. b)Exploring potential alterations of KAP1 forebrain deletion on other relevant behavioral domains, by studying the implications of this genotype on social behaviors.c)Investigating the nature of the vulnerability to stress in KAP1 KO mice, by exploring potential alterations (neuroendocrine, behavioral, neurobiological) to acute, subchronic and chronic stressors of varying intensity and nature (in interaction with objective d). d)Investigating the involvement of KRAB/KAP1-related genes in several rodent models of psychopathology (PTSD, depression, pathological aggression), by studying alterations in those genes in wild-type animals submitted to such models and by studying the behavioral consequences in KAP1 mutant mice submitted to these models. e)Defining better the contribution of KRAB/KAP1-related genes by studying the responses of newly developed genetically modified mice (i.e., late knockout, overexpression of unregulated genes, re-introduction of KAP1, etc.) on those situations providing major results under objectives a-d. 3. To test the influence of genetic polymorphism on stress-related behaviors and cognitive functions in humans A high-density genetic mapping effort will be directed towards the identification of putative polymorphisms in KAP1, KRAB-ZFP genes, and human orthologues of genes found to be dysregulated in the brain of KAP1 knockout mice. Populations under study will include:a) 450 healthy Swiss subjects previously investigated for episodic memory, emotional memory, working memory, and attention.b) 200 subjects who experienced highly emotional, stressful events (survivors of the 1994 Rwandan genocide, about 60% of whom suffer from post-traumatic stress syndrome), already investigated for traumatic memory, anxiety, and depression, to whom 200 new subjects will be added. c) 500 healthy Swiss subjects tested for episodic and emotional memory along with stress- and anxiety status, symptoms of depression and cortisol levels (to control for the actual stress status). 4. To explore the value of neuroimaging (fMRI) for the analysis of stress-related molecular parameters.In the context of another project, fMRI scans and DNA are currently acquired from about 100 healthy human subjects during emotional memory tasks. These data will be available for the analysis of genotype-dependent differences in brain activations of genetic variants identified in the present project.
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