Biology of Repetitive Sequences

Genome dynamics

Chromatin can be viewed as a highly complex mixture of proteins and nucleic acids that orchestrate DNA-based processes in the eukaryotic genome. Most of the mammalian genome is assembled into heterochromatin, a ‘closed’ structure imposed by several enzymatic activities. Such activities act on histones and the DNA itself to impinge on transcription, replication or repair.
Most of the heterochromatic fraction of the genome can be found at critical loci. These include telomeres, repetitive sequences around centromeres and a portion (about half) of the gene units encoding ribosomal RNAs. Defects in the regulation of these loci have therefore disastrous consequences on cell identity and can lead to developmental problems, cancer, premature aging or immune deficiencies. How precisely heterochromatic enzymes affect the composition of target loci has remained elusive and research in our laboratory primarily focuses on this question.
To understand how heterochromatin acts at the molecular level, we are looking at the effect of abrogating important heterochromatic activities, such as histone and/or DNA methyl-transferases, on the overall composition of key heterochromatic loci (telomeres, pericentromeres and rDNA).

PUBLICATIONS OF THE TEAM

Telomeric Chromatin and TERRA.

Barral A, Déjardin J

Purification and enrichment of specific chromatin loci.

Gauchier M, van Mierlo G, Vermeulen M, Déjardin J

Locus-specific chromatin isolation.

Vermeulen M, Déjardin J

Remodeling and destabilization of chromosome 1 pericentromeric heterochromatin by SSX proteins.

Traynor S, Møllegaard NE, Jørgensen MG, Brückmann NH, Pedersen CB, Terp MG, Johansen S, Dejardin J, Ditzel HJ, Gjerstorff MF

SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite.

Dion C, Roche S, Laberthonnière C, Broucqsault N, Mariot V, Xue S, Gurzau AD, Nowak A, Gordon CT, Gaillard MC, El-Yazidi C, Thomas M, Schlupp-Robaglia A, Missirian C, Malan V, Ratbi L, Sefiani A, Wollnik B, Binetruy B, Salort Campana E, Attarian S, Bernard R, Nguyen K, Amiel J, Dumonceaux J, Murphy JM, Déjardin J, Blewitt ME, Reversade B, Robin JD, Magdinier F

Integrative Proteomic Profiling Reveals PRC2-Dependent Epigenetic Crosstalk Maintains Ground-State Pluripotency.

van Mierlo G, Dirks RAM, De Clerck L, Brinkman AB, Huth M, Kloet SL, Saksouk N, Kroeze LI, Willems S, Farlik M, Bock C, Jansen JH, Deforce D, Vermeulen M, Déjardin J, Dhaenens M, Marks H

Telomere chromatin establishment and its maintenance during mammalian development.

Tardat M, Déjardin J

The molecular basis of the organization of repetitive DNA-containing constitutive heterochromatin in mammals

Nishibuchi G, Déjardin J.

Proteome Characterization of a Chromatin Locus Using the Proteomics of Isolated Chromatin Segments Approach

Kan SL, Saksouk N, Déjardin J

Histone H4K20 tri-methylation at late-firing origins ensures timely heterochromatin replication

Brustel J, Kirstein N, Izard F, Grimaud C, Prorok P, Cayrou C, Schotta G, Abdelsamie AF, Déjardin J, Méchali M, Baldacci G, Sardet C, Cadoret JC, Schepers A, Julien E.

The cell proliferation antigen Ki-67 organises heterochromatin

Sobecki M, Mrouj K, Camasses A, Parisis N, Nicolas E, Llères D, Gerbe F, Prieto S, Krasinska L, David A, Eguren M, Birling MC, Urbach S, Hem S, Déjardin J, Malumbres M, Jay P, Dulic V, Lafontaine DL, Feil RP, Fisher D

Nuclear-Receptor-Mediated Telomere Insertion Leads to Genome Instability in ALT Cancer

Marzec, P., Armenise, C., Perot, G., Roumelioti, F.M., Basyuk, E., Gagos, S., Chibon, F., Dejardin, J.

Constitutive heterochromatin formation and transcription in mammals

Saksouk N, Simboeck E, Déjardin J.

End-targeting proteomics of isolated chromatin segments of a mammalian ribosomal RNA gene promoter

Ide, S., Dejardin, J.

Switching between Epigenetic States at Pericentromeric Heterochromatin

Dejardin, J.

Redundant Mechanisms to Form Silent Chromatin at Pericentromeric Regions Rely on BEND3 and DNA Methylation

Saksouk N, Barth TK, Ziegler-Birling C, Olova N, Nowak A, Rey E, Mateos-Langerak J, Urbach S, Reik W, Torres-Padilla ME, Imhof A, Déjardin J.

How chromatin prevents genomic rearrangements: Locus colocalization induced by transcription factor binding.

Dejardin, J.

KAN Sophie
KAN Sophie

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GAUCHIER Mathilde
GAUCHIER Mathilde

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PLINET Mathilde
PLINET Mathilde
Dendris

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GUINTINI Laëtitia
GUINTINI Laëtitia

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REY Elodie
REY Elodie

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NOWAK Agnieszka
NOWAK Agnieszka

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ARMENISE Claudia
ARMENISE Claudia

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SIMBOECK Elisabeth
SIMBOECK Elisabeth

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GARROTE SANCHEZ Marine
GARROTE SANCHEZ Marine
La Découverte (Decazeville, 12)

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SOLETTI Marin
SOLETTI Marin

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ERC consolidator grant 2016: ‘METACHROM’

logo ercMetastable epialleles are alleles that are variably expressed in genetically identical individuals. These epialleles are established during early development by epigenetic modifications in a process influenced by stress and the environment. The epiallele’s state can subsequently be maintained throughout development and adult life. Studying the mechanisms underlying establishment and maintenance of chromatin states is critical to understanding how the environment can shape the epigenome and how it can impact on diseases and aging. Most mouse metastable epialleles result from a nearby insertion of an endogenous retrovirus, which induces position effect variegation. In mouse embryonic stem cells, these elements are silenced by the histone methyl-transferase SETDB1 which imparts heterochromatin features by tri-methylating histone H3 on lysine 9. In the same cells, telomeric H3K9me3 is also installed by SETDB1 but surprisingly, we found that H3K9me3 correlates with transcriptional activity at telomeres. I hypothesize here that metastable chromatin states are controlled by H3K9me3 and associated factors, which are targeted to defined positions that can either instruct silencing, or support active expression. To understand how metastable chromatin states are regulated, we will first use a locus-specific chromatin proteomics approach to identify H3K9me3-dependent factors in the contexts of transcription or repression. Next, both pathways will be reconstituted by tethering those factors at specific positions on model genes, and maintenance of these states will be analyzed. Finally, to obtain a comprehensive picture of the metastable states establishment and maintenance, we will map heterochromatin factors genome-wide, in response to distinct stimuli in mESCs. This proposal will deepen our understanding of the mechanisms by which mammals use gene regulation to adapt to environmental conditions.