Project

Back to overview

Chromatin structure and dynamics in trinucleotide repeat instability

Applicant Dion Vincent
Number 144789
Funding scheme SNSF Professorships
Research institution Center for Integrative Genomics (CIG) Faculté de biologie et de médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Genetics
Start/End 01.10.2013 - 30.09.2017
Approved amount 1'550'587.00
Show all

All Disciplines (4)

Discipline
Genetics
Molecular Biology
Biochemistry
Cellular Biology, Cytology

Keywords (6)

Nuclear organization; DNA repair; ATP-dependent chromatin remodeling complexes; Chromatin; Genome stability; Neurodegenerative diseases

Lay Summary (French)

Lead
Au moins 17 maladies neurologiques sont causées par la présence de séquences d’ADN inhabituelles dans le génome humain. Ces syndromes incluent la dystrophie myotonique, la maladie d’Huntington, le Syndrome du X fragile, ainsi que 14 autres. Elles restent toutes sans remède.
Lay summary

Chez les individus normaux, l’ADN possède des séquences répétitives de moins de 30 unités à plusieurs endroits dans le génome. Étant courtes, ces séquences ne causent aucun problème. Par contre, chez les patients atteints de ces maladies mentales, il y a une expansion d’une de ces répétitions. Celle-ci peut atteindre plusieurs milliers d’unités et causer de graves problèmes incluant la perte progressive de neurones.  

Le but de ce projet de recherche est de comprendre comment ces séquences répétitives peuvent devenir de plus en plus longues et éventuellement avoir des effets néfastes.

En ce moment, nous savons que ces séquences répétitives ressemblent à des lésions dans l’ADN, ce qui pousse la machinerie cellulaire à réparer inutilement une séquence qui n’est pas endommagée et qui n’a pas besoin d’ajustement. Si l’on comprenait mieux le mécanisme qui mène aux changements dans la longueur des répétitions, nous pourrions l’utiliser pour induire une contraction de la séquence répétitive. Ceci éliminerait la cause de la maladie et pourrait peut-être nous donner des outils thérapeutiques contre ces maladies.   

Par conséquent, nous proposons d’identifier de nouveaux facteurs qui influencent la réparation des séquences répétitives à l’aide de méthodes génétiques dans les cellules humaines. De plus nous déterminerons le mécanisme d’actions de ces nouveaux facteurs et évaluerons s’il serait possible de les cibler à des fins thérapeutiques.

Direct link to Lay Summary Last update: 16.05.2013

Lay Summary (English)

Lead
There is a large family of human mental disorders that are caused by the presence of unusual DNA sequences in specific places in the genome. These disorders include myotonic dystrophy, Huntington disease, Fragile X syndrome, and 14 others. We have no cure for these diseases.
Lay summary

In normal individuals there are short repetitive sequences, for example, CAGCAGCAG at these genomic locations. In patients, however, these sequences have expanded (increased in length) sometimes reaching hundreds or even thousands of repetitive units. This causes serious problems and patients progressively lose neurons. We do not understand how short sequences can expand to cause the disease.

The goal of this proposal is to understand how the repetitive sequences change in length. 

We know that the expanded repeats fool the cell into thinking that it is damaged DNA, which triggers DNA repair proteins to act on these sequences when they should not. Because these sequences are repetitive in nature, they are not repaired properly, leading to changes in the length of the repeat tract. If we could better understand the genetic factors and the way they process the repeat tract, we could perhaps design a therapeutic approach aimed at shrinking the size of the repeat tract down to the size found in normal individuals. In this proposal, we aim to identify new factors involved in changing the size of the repeat tracts. Specifically, we will look for factors involved in changing the way DNA is packaged into the nucleus of a cell.

Each human cell has about 2 meters worth of DNA tightly packaged into a nucleus that is much smaller than the diameter of a hair. The amalgam of DNA and proteins that allow this compaction is called chromatin. Chromatin is important for DNA repair in ways we do not completely understand. Here we aim to test the idea that the packaging of expanded repeats is involved in their inappropriate repair and therefore in changing the repeat length. In the future, we hope to use this information to design novel therapeutic approaches for these neurological diseases.

Direct link to Lay Summary Last update: 16.05.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Contracting CAG/CTG repeats using the Cas9 nickase
Cinesi Cinzia, Aeschbach Lorène, Yang Bin, Dion Vincent (2016), Contracting CAG/CTG repeats using the Cas9 nickase, in Nature Communications, ¸7, 13272.
Tissue specificity in DNA repair: lessons from trinucleotide repeat instability.
Dion Vincent (2014), Tissue specificity in DNA repair: lessons from trinucleotide repeat instability., in Trends in genetics : TIG, 30(6), 220-9.

Collaboration

Group / person Country
Types of collaboration
Ioannis Xenarios / Swiss Institute for Bioinformatics Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Peter Meister / University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
John H. Wilson / Baylor College of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Geneviève Gourdon France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Perelman School of Medicine - University of Pensylvania United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Alexandre Reymond / Université de Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Keith Harshman / University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Aurélien Bancaud / LAAS France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Catherine Freudenreich / Tufts University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Keith Harshman / Université de Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Andrzej Stasiak / University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO meeting on DNA Topoisomerases and DNA Topology Poster Chromatin folding in expanded CAG/CTG repeat disorders 17.09.2017 Les Diablerets, Switzerland Rodriguez Lima Oscar;
LS2 satellite meeting: DNA Topoisomerases and DNA Topology Individual talk Chromatin folding in expanded repeat disorders 16.09.2017 Les Diablerets, Switzerland Rodriguez Lima Oscar;
EMBO Basel life Poster A novel inducible chromatin targeting system to study expanded CAG/CTG repeats. 10.09.2017 Basel, Switzerland Yang Bin;
11th International dystrophia myotonica consortium Poster Contracting expanded CAG/CTG repeats using the CRISPR-Cas9 nickase 05.09.2017 San Francisco, United States of America Cinesi Cinzia;
Seminar - University of Sherbrooke Individual talk Chromatin and Instability of expanded CAG/CTG repeats 16.06.2017 Sherbrooke, Canada Dion Vincent;
CIG symposium Poster A novel inducible chromatin targeting system to study expanded CAG/CTG repeats 15.06.2017 Lausanne, Switzerland Aeschbach Lorene; Cinesi Cinzia; Yang Bin;
Seminar - Centre de Recherche du CHU de Québec Individual talk Chromatin and Instability of expanded trinucleotide repeats 13.06.2017 Quebec City, Canada Dion Vincent;
GRC CAG Triplet Repeat Disorders Talk given at a conference Contracting expanded CAG/CTG repeats using the CRISPR-Cas9 nickase 06.06.2017 West Dover, United States of America Dion Vincent;
EpiGeneSwiss Poster A CRISPR screen to identify modifiers of expanded CAG/CTG repeat expression 29.05.2017 Weggis, Switzerland Rodriguez Lima Oscar;
Seminar - Institut Pasteur Individual talk Chromatin and Instability of expanded CAG/CTG repeats 20.04.2017 Paris, France Dion Vincent;
Seminar Genome Instability Group Individual talk Chromatin and instability of expanded CAG/CTG repeats 17.02.2017 Baylor College of Medicine - Houston, United States of America Dion Vincent;
Researcch Seminar - University of Oregon Individual talk Chromatin and instability of expanded trinucleotide repeats 14.02.2017 Eugene, United States of America Dion Vincent;
Friedrich Miescher Institute - Semainar Individual talk Chromatin and Instability of expanded trinucleotide repeats 25.11.2016 Basel, Switzerland Dion Vincent;
Research Seminar - Roche Individual talk Chromatin structure and trinucleotide repeat instability 25.08.2016 Basel, Switzerland Dion Vincent;
2016 Dynamic DNA Structures in Biology FASEB Summer Research Conference Talk given at a conference Contracting CAG/CTG repeats using the Cas9 nickase 10.07.2016 Saxton River, United States of America Dion Vincent;
Swiss Meeting on Genome Stability and Chromatin Dynamics 2016 Talk given at a conference Contracting CAG/CTG repeats using the Cas9 nickase 08.06.2016 Emmetten, Switzerland Cinesi Cinzia;
EpiGeneSwiss Talk given at a conference Chromatin structure in expanded trinucleotide repeat instability 06.06.2016 Weggis, Switzerland Yang Bin; Rodriguez Lima Oscar; Dion Vincent;
Gordon Research Conference on Chromatin Structure & Function Poster Chromatin conformation of expanded trinucleotide repeats in myotonic dystrophy type 1 22.05.2016 Les Diablerets, Switzerland Dion Vincent; Yang Bin;
10th Quinquennial Conference on Responses to DNA damage: from molecule to disease Talk given at a conference Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase 17.04.2016 Egmond aan Zee, Netherlands Dion Vincent;
University of St-Andrews - seminar Individual talk Chromatin structure and Trinucleotide repeat instability 24.02.2016 St-Andrews, Great Britain and Northern Ireland Dion Vincent;
INTERNATIONAL MYOTONIC DYSTROPHY CONSORTIUM MEETING Poster Are Zinc Finger Nucleases suitable therapeutic agents against myotonic dystrophy type 1? 08.10.2015 Paris, France Cinesi Cinzia;
CIG Symposium 2015: A decage in Genomics Poster A novel chromatin targeting system to study trinucleotide repeat instability 11.06.2015 Lausanne, Switzerland Dion Vincent; Aeschbach Lorene; Yang Bin;
Séminaires du Départment de Biologie Cellulaire, UNIGE - Host: Françoise Stutz Individual talk Trinucleotide repeat instability: Location, Location, Location... and also chromatin 01.06.2015 Université de Genève, Switzerland Dion Vincent;
Understanding the Genome III Talk given at a conference Chromatin modifying enzymes in trinucleotide repeat instability 20.03.2015 Lavaux, Switzerland Dion Vincent;
Genomic Instability and DNA Repair (X4) Poster A novel chromatin targeting system to study trinucleotide repeat instability 01.03.2015 Whistler, Canada Dion Vincent;
Unstable Microsatellite and Human Disease Poster A novel chromatin targeting system to study trinucleotide repeat instability 17.01.2015 Guanacaste, Costa Rica Yang Bin;
GDSC Seminars - Host: Jessica Downs Individual talk Organizing DNA repair in a 3D nucleus 08.10.2014 University of Sussex, Great Britain and Northern Ireland Dion Vincent;
Manipulating the Genome: Over 40 Years of Unwinding the Helix Talk given at a conference Repairing DNA in Chromatin 27.07.2014 Houston, United States of America Dion Vincent;
CIG Symposium 2014: The theory of regulatory cycles and the cell cycle Poster Chromatin remodeling in trinunucleotide repeat instability 12.06.2014 Lausanne, Switzerland Dion Vincent; Yang Bin;
Swiss Meeting on Genome Stability and Chromatin Dynamics 2014 Talk given at a conference ATP-dependent chromatin remodeling enzymes in trinucleotide repeat instability 26.05.2014 Waggis, Switzerland Yang Bin; Dion Vincent;
Gordon Research Conference on DNA Damage, Mutation & Cancer Poster Repairing DNA in chromatin 16.03.2014 Ventura, United States of America Dion Vincent;
10th Course on Epigenetics Talk given at a conference Chromatin structure and dynamics in trinucleotide repeat instability 12.03.2014 Paris, France Yang Bin;
Changins meeting 2013 "Epigenetics: Mechanisms and clinical applications”. Poster Chromatin remodeling in Trinucleotide repeat instability 21.11.2013 Changins, Switzerland Yang Bin; Dion Vincent;


Self-organised

Title Date Place
EpiGeneSwiss meeting 2017 29.05.2017 Weggis, Switzerland
Lausanne Genomics Days 2017 09.02.2017 Lausanne, Switzerland
EpiGeneSwiss 06.06.2016 Weggis, Switzerland
From a single cell to a complex organism 02.06.2016 Lausanne, Switzerland
Lausanne Genomics Days 2016 18.02.2016 Lausanne, Switzerland
Lausanne Genomics Days 2015 12.02.2015 Lausanne, Switzerland
Manipulating the Genome: Over 40 Years of Unwinding the Helix 27.07.2014 Houston, United States of America

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Ces Ciseaux moléculaires ont révolutioné la génétique Allez Savoir Western Switzerland 2017
Media relations: radio, television Des "ciseaux génétiques" qui pourraient révolutionner le futur de la médecine RTS la première - CQFD Western Switzerland 2017
Media relations: radio, television Crispr: des ciseaux moléculaires pour le traitement des maladies neurologiques RST la première - CQFD Western Switzerland 2016
Talks/events/exhibitions Passeport Vacances Western Switzerland 2015
Media relations: print media, online media Trois Lauréats pour un prix Nobel Le Temps Western Switzerland 2015
Talks/events/exhibitions Passeport vacances Western Switzerland 2014

Awards

Title Year
Postdoctoral fellowship in a foreign country. Granted by CONACyT (Mexico) 2017
Young Investigator Award for best poster at the 11th International Myotonica Dystrophia Consortium 2017
Researcher of the Month - GeneSuisse - https://www.gensuisse.ch/fr/blog/prof-vincent-dion-center-integrative-genomics-universit%C3%A9-de-lausanne 2016

Associated projects

Number Title Start Funding scheme
172936 Manipulating trinucleotide repeat instability 01.10.2017 SNSF Professorships
172936 Manipulating trinucleotide repeat instability 01.10.2017 SNSF Professorships

Abstract

Expansion of trinucleotide repeats is the underlying cause of at least 17 human neurological disorders for which no cure exists. The length of the repeat tract is proportional to the severity of the disease and thus understanding how repeats change in length will facilitate the design of therapeutics. Unfortunately, the mechanisms underlying trinucleotide repeat instability remain obscure. Recent evidence suggests that DNA packaging into chromatin has a significant impact on repeat instability. This proposal tests the hypothesis that local changes in chromatin structure impact trinucleotide repeat expansion by affecting how the DNA repair machinery processes these unusual DNA sequences.Using cultured human cells, we will:1) Create a novel gain-of-function assay to distinguish between direct and indirect effects of chromatin modifiers on trinucleotide repeat instability.2) Uncover new factors involved in trinucleotide instability and determine how they work with the DNA repair machinery to cause repeat length changes.3) Determine whether there are changes in nuclear organization at the disease loci upon expansion and whether nuclear organization influences TNR instability.The experiments proposed herein take advantage of a powerful assay system to further our understanding of TNR instability. Furthermore, we will establish TNR instability as a model to study how chromatin organization and dynamics impact DNA repair. Indeed, chromatin structure has profound effects on DNA repair processes that are only poorly understood. The results of this study will provide unique insights into DNA repair mechanisms because, unlike most approaches used to study DNA repair, we will investigate how the normal DNA repair machinery acts on an abnormal substrate composed of repetitive sequences.
-