Project

Back to overview

The role of Lsm proteins in heterochromatic gene silencing

Applicant Mattout Anna
Number 151381
Funding scheme Marie Heim-Voegtlin grants
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Genetics
Start/End 01.06.2014 - 30.09.2016
Approved amount 221'884.00
Show all

Keywords (7)

gene regulation; nuclear mRNA decay; Post-transcriptional gene silencing (PTGS); Lsm proteins; heterochromatin silencing; RNA processing; C.elegans

Lay Summary (French)

Lead
Le rôle des protéines Lsm dans la répression de l’expression de l’hétérochromatineLes gènes (ADN) exprimés sont transcrits en molécules d’ARN puis, dans la plupart des cas, traduits en protéines. La régulation de l’expression des gènes s’effectue à plusieurs niveaux et est essentielle puisque chaque cellule d’un organisme possède exactement les mêmes gènes; mais différents gènes s’expriment dans différentes cellules en fonction du type de cellule ou de l’environnement. Dans ce projet de recherche nous voulons mettre à jour et mieux comprendre un nouveau mécanisme de régulation de l’hétérochromatine qui est la partie la plus compacte du génome et dont l’expression est globalement très réprimée.
Lay summary

Contenu et objectifs du travail de recherche

Actuellement, la répression de l’hétérochromatine est principalement expliquée par une régulation au niveau transcriptionnel, qui implique que les séquences d’ADN de l’hétérochromatine ne sont pas ou très peu transcrites en molécules d’ARN.  Chez la levure d’autres mécanismes post-transcriptionnels ont aussi été démontrés, et ce projet tente de prouver que ceci est aussi le cas chez les animaux pluricellulaires. C’est pourquoi le projet porte sur les protéines Lsm dont certaines ont été identifiées récemment comme étant responsable de la répression de gènes reporters ayant des caractéristiques hétérochromatiques, et ces proteines sont connues pour leur fonctions biologiques au niveau post-transcriptionnel, entre autres importantes pour la dégradation de molécules d’ARN.

Au cours d’une première phase, nos recherches s’intéresseront aux différents complexes de protéines Lsm et nous essaierons d’identifier lequel est responsable de cette régulation génique et à quel point ce phénomène est spécifique pour les régions hétérochromatiques. Au cours d’une deuxième phase, nous essaierons d’élucider le mécanisme par lequel ces protéines agissent.

Contexte scientifique et social du projet de recherche

Le projet relève de la recherche fondamentale. Pour mieux comprendre la régulation des gènes qui est essentiel à la vie, il est important d’étudier de potentiels nouveaux mécanismes dans notre cas, chez le ver C.elegans puis de vérifier si ce mécanisme est aussi utilisé chez les mammifères, ce qui est très plausible puisque les protéines Lsm sont présentes et très similaires chez le ver et les mammifères.

Direct link to Lay Summary Last update: 12.02.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Chromatin states and nuclear organization in development — a view from the nuclear lamina
Mattout Anna, Cabianca Daphne S., Gasser Susan M. (2015), Chromatin states and nuclear organization in development — a view from the nuclear lamina, in Genome Biology, 16(1), 174-199.

Collaboration

Group / person Country
Types of collaboration
Prof. Motti Choder /Technion, Israel Israel (Asia)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Helge Grosshans/FMI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
IMB Conference on Epigenetics in Development. Poster The RNA binding LSM2-8 complex mediates heterochromatin silencing in differentiated C. elegans cells 20.10.2016 Mainz, Germany Mattout Anna;
Chromatin Structure & Function Gordon Research Conference Poster The RNA binding LSM2-8 complex mediates heterochromatin silencing in differentiated C. elegans cells 22.05.2016 les Diablerets, Switzerland Mattout Anna;
Personal scientific discussion (~2H) with Motti Choder one of the best expert in the field of the Lsm project Individual talk The role of Lsm proteins in heterochromatic gene silencing 12.12.2014 FMI, Basel, Switzerland Mattout Anna;
EMBO EMBL SYmposium on The Complex life of mRNA Individual talk Individual talk with Sebastian Kadener (expert in RNA field form my previous institute) 05.10.2014 Heidelberg, Germany Mattout Anna;
FMI annual meeting Poster The role of Lsm proteins in Heterochormatic gene silencing 17.09.2014 Pontresina, Switzerland Mattout Anna;
Gordon Research Conference on Post-Transcriptional Gene Regulation Poster The role of Lsm proteins in heterochromatic gene silencing 13.07.2014 Salve Regina University, RI, United States of America Mattout Anna;


Self-organised

Title Date Place
FMI Postdoc Seminar Series 2014 12.12.2014 FMI, Switzerland

Associated projects

Number Title Start Funding scheme
168717 The role of LSM proteins in heterochromatic gene silencing 01.10.2016 Marie Heim-Voegtlin grants

Abstract

Regulation of gene expression includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA), as dictated by cell type and environment. The occurrence of heterochromatin in eukaryotic genomes is a universal mode of action for the repression of repetitive DNA elements and of genes found in it. To date, transcriptional repression is believed to be the main -if not the only - mechanism responsible for ensuring stable repression. However, additional mechanisms that silence heterochromatic genes at the co- or post-transcriptional level may exist, and in this project we intend to get a better understanding of these. In a genome-wide derepression screen of a silent, repetitive gene array in C. elegans, among the expected chromatin regulators, we identified a number of unexpected hits, such as three Lsm proteins (Towbin et al., 2012). Lsm proteins are evolutionarily conserved proteins that bind RNA. They assemble in two major complexes, the Lsm1-7 and Lsm2-8 complexes, which function in aspects of RNA processing. Namely, the Lsm1-7 complex is involved in cytoplasmic mRNA decay and the Lsm2-8 complex regulates both nuclear pre-mRNA decay and U6 snRNA stability (Beggs et al., 2005; Tharun et al., 2009). In our attempt to study the role of Lsm proteins in heterochromatic gene silencing, we found recently that in C. elegans Lsm-2, -5, -6 and -7 are required for silencing within heterochromatic regions independently of the location in the genome, and of the sequence of the coding regions or of the regulatory elements. In contrast, Lsm-1 and other proteins involved in cytoplasmic mRNA degradation are not required for this same heterochromatic gene repression. Moreover, lsm-7 knock-down on top of mutant strains lacking key heterochromatin factors, such as H3K9me3 has a synergistic effect for heterochromatic transgene derepression or cause a premature synthetic lethality, suggesting the existence of an additional mechanism involving the Lsm proteins which is independent of the H3K9me3-related transcriptional repression mechanism. Therefore, we hypothesize that heterochromatic gene silencing could occur very probably through the Lsm2-8 complex, since Lsm-1 is not required, by targeting leaky heterochromatic transcripts to 5’ to 3’ RNA degradation in the nucleus. This proposed mechanism could serve as a back-up mechanism in abnormal conditions, for example, when transcriptional repression is impaired. Obviously, we propose to test this new hypothesis, and our main goals in this project will be to understand: Which of the Lsm proteins are involved in the heterochromatic gene silencing, and which other co-factors? What the Lsm proteins are silencing? How does the Lsm complex of interest silence heterochromatic transgenes? And is it a conserved mechanism in mammals? Answering to those questions will provide knowledge on a very novel mechanism involved in gene silencing in heterochromatic regions which will broaden our understanding of gene regulation in general.
-