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Studies on the role of RNAi and other RNA turnover mechanisms in initiation and maintenance of heterochromatin

English title Studies on the role of RNAi and other RNA turnover mechanisms in initiation and maintenance of heterochromatin
Applicant Bühler Marc
Number 139204
Funding scheme SNSF Professorships
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.06.2012 - 31.05.2014
Approved amount 785'450.00
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All Disciplines (4)

Discipline
Molecular Biology
Cellular Biology, Cytology
Genetics
Biochemistry

Keywords (6)

Dicer; RNA interference; non-coding RNA; Epigenetics; Genome regulation; Gene silencing

Lay Summary (English)

Lead
Lay summary

Although it may seem paradoxical, there is growing evidence that RNA is actively involved in the formation of silent chromatin. Classic examples where RNA is linked to chromatin-dependent processes include dosage compensation and genomic imprinting in mammals. More recently, small RNAs (sRNAs), the molecules common to all RNAi-related pathways, have been found to have a major impact on chromatin by guiding histone or DNA modification. This can introduce heritable variation into gene expression without altering the DNA sequence itself, forming the foundation of epigenetic phenomena. Thus, sRNAs harbour the potential to permanently shut down genes, in addition to just silencing them temporarily.

In this project, we focus our studies on Dicer, the enzyme responsible for generating sRNAs. The project is based on our observations that nuclear retention of fission yeast Dicer is a prerequisite for a functional heterochromatin assembly pathway and that Dicer accumulates at the nuclear periphery in association with pores. We are performing experiments with fission yeast that focus on elucidating the molecular details of the nuclear retention mechanism and to investigate the functional relevance of the perinuclear localization of Dicer. This project will further our understanding of epigenetic genome regulation and the spatial organization of RNAi pathways in general.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Regulation of Transcription through Acetylation of H3K122 on the Lateral Surface of the Histone Octamer
Tropberger Philipp, Pott Sebastian, Keller Claudia, Kamieniarz-Gdula Kinga, Caron Matthieu, Richter Florian, Li Guohong, Mittler Gerhard, Liu Edison T., Buehler Marc, Margueron Raphael, Schneider Robert (2013), Regulation of Transcription through Acetylation of H3K122 on the Lateral Surface of the Histone Octamer, in CELL, 152(4), 859-872.
A detour to mature.
Stunnenberg Rieka, Bühler Marc (2012), A detour to mature., in Molecular cell, 46(6), 719-21.
Dynamic nature of heterochromatin highlighted by a HP1Swi6- dependent gene silencing mechanism
Bühler M, Hiller S (2012), Dynamic nature of heterochromatin highlighted by a HP1Swi6- dependent gene silencing mechanism, in Cell Cycle, 11(21), 3907-3908.
HP1(Swi6) mediates the recognition and destruction of heterochromatic RNA transcripts.
Keller Claudia, Adaixo Ricardo, Stunnenberg Rieka, Woolcock Katrina J, Hiller Sebastian, Bühler Marc (2012), HP1(Swi6) mediates the recognition and destruction of heterochromatic RNA transcripts., in Molecular cell, 47(2), 215-27.
RNAi keeps Atf1-bound stress response genes in check at nuclear pores
Woolcock KJ, Stunnenberg R, Gaidatzis D, Hotz H-R, Emmerth S, Barraud P, Bühler M (2012), RNAi keeps Atf1-bound stress response genes in check at nuclear pores, in Genes and Development, 26(7), 683-692.
Schizosaccharomyces pombe reporter strains for relative quantitative assessment of heterochromatin silencing
Shimada Y, Bühler M (2012), Schizosaccharomyces pombe reporter strains for relative quantitative assessment of heterochromatin silencing, in Yeast, 29(8), 335-341.
Nuclear organisation and RNAi in fission yeast.
Woolcock Katrina J, Bühler Marc, Nuclear organisation and RNAi in fission yeast., in Current opinion in cell biology.

Collaboration

Group / person Country
Types of collaboration
University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Non-coding RNA, epigenetics and transgenerational inheritance Talk given at a conference Non-coding RNA function in the fission yeast nucleus 11.04.2013 Cambridge, UK, Great Britain and Northern Ireland Bühler Marc;
RNA biology distinguished seminar series Individual talk Of long and short non-coding RNAs 28.03.2013 Sherbrooke University, Canada, Canada Bühler Marc;
Seminar EMBL Grenoble Individual talk Non-coding RNA function in the fission yeast nucleus 01.03.2013 Grenoble, France, France Bühler Marc;
Keystone Symposia “Noncoding RNAs in Development and Cancer” Talk given at a conference RNA-mediated eviction of a heterochromatin protein 20.01.2013 Vancouver, CA, Canada Bühler Marc;
Cell Symposia: Functional RNAs Talk given at a conference RNA-mediated eviction of a heterochromatin protein 02.12.2012 Sitges, Spain, Spain Bühler Marc;
Seminar MRC Clinical Sciences Centre, London Individual talk Shaping the epigenome with the help of ncRNAs 14.11.2012 London, UK, Great Britain and Northern Ireland Bühler Marc;
Seminar CIG, University of Lausanne Individual talk Shaping the epigenome with the help of ncRNAs 28.08.2012 Lausanne, Switzerland, Switzerland Bühler Marc;
Summer school, University of Aarhus Talk given at a conference ncRNA and Chromatin 06.08.2012 Aarhus, Denmark, Denmark Bühler Marc;
mitoNET-Congress: Mitochondrial Medicine 2012 Talk given at a conference Towards a better mechanistic understanding of Friedreich's Ataxia 12.07.2012 Bern, Switzerland, Switzerland Bühler Marc;
Seminar DKFZ/ZMBH Heidelberg Individual talk CTGS: degrading RNA in association with chromatin 28.06.2012 Heidelberg, Germany, Germany Bühler Marc;
EMBO Conference on Gene Transcription in Yeast Talk given at a conference Genome control by RNA turnover 16.06.2012 St. Feliu de Guixols, Spain, Spain Bühler Marc;
Seminar/Lecture, Institute Curie Paris, France Individual talk Work on Non-coding Genome 05.06.2012 Paris, France, France Bühler Marc;


Associated projects

Number Title Start Funding scheme
119193 Studies on the role of RNAi and other RNA turnover mechanisms in initiation and maintenance of heterochromatin 01.06.2008 SNSF Professorships

Abstract

I am applying for a 2 year prolongation of my SNF professorship to follow up on our previous work on the fission yeast Dicer protein. Dicer is a key enzyme in the RNAi pathway and is required for formation of heterochromatin at fission yeast centromeres. The proposed experiments are based on our observations that nuclear retention of Dicer is a prerequisite for a functional heterochromatin assembly pathway and that Dicer accumulates at the nuclear periphery in association with pores. I am proposing yeast genetics, proteomics and genomics experiments that focus on elucidating the molecular details of the nuclear retention mechanism and to investigate the functional relevance of the perinuclear localization of Dicer. This project is a logic continuation of our previous work and will further our understanding of the spatial regulation of RNAi pathways in general.
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