Project

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Mechanisms of transcriptional memory in response to developmental and environmental stimuli

Applicant Paro Renato
Number 143922
Funding scheme Project funding (Div. I-III)
Research institution Computational Systems Biology Department of Biosystems, D-BSSE ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Molecular Biology
Start/End 01.04.2013 - 31.03.2016
Approved amount 737'742.00
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Keywords (4)

epigenetics; gene regulation; Polycomb/Trithorax; Hsp90

Lay Summary (English)

Lead
Lay summary

Background:

Developmental decisions, defining lineage-specific expression patterns, need to be preserved during cell division. This process, termed “cellular or transcriptional memory”, is controlled at the level of chromatin. Two groups of chromatin proteins are responsible for maintaining the differential gene expression patterns characterizing the individual cell types. The Polycomb group (PcG) proteins are required for a stable and heritable silencing of target genes. Conversely, the proteins of the Trithorax group (TrxG) counteract PcG repression and maintain the active expression state. Signals restricted in space and time initiate developmental choices, which are then subsequently maintained by the PcG/TrxG controlled chromatin functions. Hence, the interplay between these chromatin regulators utilizes epigenetic features and forms the molecular basis for the heritability of cell identities. PcG/TrxG chromatin control has been evolutionary highly conserved, ranging from flower development in plants to X chromosome inactivation in mammals. A major site of action for these epigenetic regulators is at promoters of target genes, in particular at promoters with a paused polymerase. PcG protein complexes place and bind histone modifications at repressed target genes, resulting in a reduced accessibility of the nucleosomal structure and in an inhibition of the transcriptional elongation process. The counteracting TrxG proteins exhibit functions, which open nucleosomal structures and allow the transcriptional machinery to enter processivity. Interestingly, we observed that Hsp90, a molecular chaperone and important sensor of environmental stress signals, cooperate with the PcG/TrxG system at paused polymerases.

 

Goals:

Our understanding of transcriptional memory stems primarily from the involvement of the PcG and TrxG in maintaining developmental decisions. In this project we would like to expand the view by analyzing whether environmentally induced stress conditions can impose epigenetically heritable gene expression states. We will used cellular systems inducible by environmental stimuli and combine new methodologies, like GRO-seq and PAR-CLIP, to study the dynamic behavior of PcG and TrxG proteins at target promoters and identify the crosstalk between the two groups at the transition from silenced to activated state. This will include the identification and functional analysis of non-coding RNAs found as important companions of PcG-induced repression. We will develop transgenic reporter systems in Drosophila sensing environmental cues and measure whether stress conditions can be imprinted into chromatin and epigenetically inherited through mitosis and eventually even meiosis.

 

Relevance:

Several epidemiological reports have suggested that environmental exposures early in development play a critical role in susceptibility to late-onset diseases such as diabetes and cancer. Some of these conditions may even be inherited to future generations. Hence, an important question is whether environmental stimuli can induce chromatin states, which are heritable in a similar fashion as developmental signal induce the maintenance of cellular identities. Given that several Hsp90 inhibitors are in clinical trials as anti-cancer drugs, it will also be important to further assess the molecular crosstalk this chaperone exerts with the PcG/TrxG system in controlling developmental and stress-induced genes.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The legacy of Drosophila imaginal discs
Beira Jorge V., Paro Renato (2016), The legacy of Drosophila imaginal discs, in Chromosoma, 1-20.
The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing
Degrauwe Nils, Schlumpf Tommy B., Janiszewska Michalina, Martin Patricia, Cauderay Alexandra, Provero Paolo, Riggi Nicolo, Suvà Mario-L., Paro Renato, Stamenkovic Ivan (2016), The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing, in Cell Reports, 15(8), 1634-1647.
Ectopic expression of Msx2 in mammalian myotubes recapitulates aspects of amphibian muscle dedifferentiation.
Yilmaz Atilgan, Engeler Rachel, Constantinescu Simona, Kokkaliaris Konstantinos D, Dimitrakopoulos Christos, Schroeder Timm, Beerenwinkel Niko, Paro Renato (2015), Ectopic expression of Msx2 in mammalian myotubes recapitulates aspects of amphibian muscle dedifferentiation., in Stem cell research, 15(3), 542-53.
High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins.
Comoglio Federico, Schlumpf Tommy, Schmid Virginia, Rohs Remo, Beisel Christian, Paro Renato (2015), High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins., in Cell reports, 11(5), 821-34.
Trithorax and Polycomb group-dependent regulation: a tale of opposing activities.
Geisler Sarah J, Paro Renato (2015), Trithorax and Polycomb group-dependent regulation: a tale of opposing activities., in Development (Cambridge, England), 142(17), 2876-87.
Transcriptional silencing by polycomb-group proteins.
Grossniklaus Ueli, Paro Renato (2014), Transcriptional silencing by polycomb-group proteins., in Cold Spring Harbor perspectives in biology, 6(11), 019331-019331.
Polycomb group protein bodybuilding: working out the routines.
Sievers Cem, Paro Renato (2013), Polycomb group protein bodybuilding: working out the routines., in Developmental cell, 26(6), 556-8.

Collaboration

Group / person Country
Types of collaboration
Dirk Schübeler/FMI Switzerland (Europe)
- Research Infrastructure
John Lis/Cornell University/USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
EPIGENESYS/Curie Institute/Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Niko Beerenwinkel/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Remo Rohs United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Ivan Stamenkovic Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Timm Schröder Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Ruedi Aebersold IMSB/ETHZ 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
Swiss RNA Meeting Poster IMP2 prevents let-7 mediated silencing in the absence of LIN28AB 22.01.2016 Bern, Switzerland Schlumpf Tommy;
Rabelais Symposium Talk given at a conference Cellular memory in regeneration and cancer 20.11.2015 Montpellier, France Paro Renato;
Skin Repair Symposium Talk given at a conference Cellular memory in regeneration and cancer 31.10.2015 Basel, Switzerland Paro Renato;
ZMBH Symposium Talk given at a conference Cellular memory in regeneration and cancer 18.09.2015 Heidelberg, Germany Paro Renato;
Umea University Seminar Individual talk Cellular memory in regeneration and cancer 11.09.2015 Umea, Sweden Paro Renato;
DBM Symposium Talk given at a conference Cellular memory in regeneration and cancer 21.08.2015 Basel, Switzerland Paro Renato;
EMBO Conference: Developmental Circuits Talk given at a conference Cellular memory in regeneration, cancer and aging 28.05.2015 Krete, Greece Paro Renato;
Swiss Drosophila Meeting 2015 Poster hsp70: a model gene to study resilencing of activated genes by Polycomb group proteins 24.04.2015 Lausanne, Switzerland Pereira Allwyn;
MPI Freiburg Epigenetics Meeting Talk given at a conference Profiling chromatin-associated RNA-protein interactions by PAR-CLIP 05.12.2014 Freiburg, Germany Paro Renato;
Actelion Seminar Individual talk Epigenetic memory 25.11.2014 Allschwil, Switzerland Paro Renato;
IMB Conference Nuclear RNA in Gene Regulation & Chromatin Structure Talk given at a conference Profiling chromatin-associated RNA-protein interactions by PAR-CLIP 11.10.2014 Mainz, Germany Paro Renato;
UKBB Research Day Talk given at a conference Epigenomics in Basic and Clinical Research 18.09.2014 Basel, Switzerland Paro Renato;
CLINAM Conference Talk given at a conference The Power of Next Generation Sequencing 23.06.2014 Basel, Switzerland Paro Renato;
LMU Munich - Faculty of Biology Keynote Seminar Series Individual talk Epigenetic memory in regeneration and cancer 21.06.2014 Munich, Germany Paro Renato;
EPIGEN chromatin Seminars Talk given at a conference Epigenetic memory in regeneration and cancer 16.06.2014 Palermo, Italy Paro Renato;
Seminar University of Geneva Individual talk Epigenetic memory in regeneration and cancer 16.05.2014 Geneva, Switzerland Paro Renato;
EMBO Conference: Chromatin & Epigenetics Talk given at a conference Cellular memory in regeneration and cancer 08.05.2014 Heidelberg, Germany Paro Renato;
DKFZ-ZMBH Alliance Meeting Talk given at a conference Epigenetic memory in regeneration and cancer 25.04.2014 Heidelberg, Germany Paro Renato;
Cell Biology Seminars Individual talk Epigenetic memory in regeneration and cancer 31.03.2014 Bern, Switzerland Paro Renato;
Molecular Mechanisms in Development and Evolution Talk given at a conference Epigenetic memory in regeneration and cancer 22.03.2014 Basel, Switzerland Paro Renato;
Swiss RNA Meeting Poster Towards the identification of RNA-interacting PcG proteins 24.01.2014 Bern, Switzerland Schlumpf Tommy;
Epigenetics Day Talk given at a conference Epigenetic memory in regeneration and cancer 27.11.2013 Kaust, Saudi Arabia Paro Renato;
European Drosophila Research Conference 2013 Poster S'ph'reading into the gene body: a novel role for ph in gene expression control? 16.10.2013 Barcelona, Spain Pereira Allwyn;
Annual Symposium German Genetics Society Talk given at a conference Epigenetic memory in regeneration and cancer 23.09.2013 Braunschweig, Germany Paro Renato;
SKMB Gene Regulation Workshop Poster PAR-CLIP as a method to screen PcG proteins for RNA-binding 04.09.2013 Lausanne, Switzerland Schlumpf Tommy;
TRR81 Symposium Talk given at a conference Epigenetic memory in regeneration and cancer 02.09.2013 Zuderduin, Netherlands Paro Renato;
talk IGBMC Strasbourg Individual talk Genome instability is not observed in neoplastic growth caused by a deregulated epigenetic network in Drosophila 26.06.2013 Strasbourg, France Paro Renato;
Gordon Research Conference: Tissue repair and regeneration, USA Talk given at a conference Epigenetic memory in regeneration and cancer 15.06.2013 New London, NH, United States of America Paro Renato;
Humboldt Graduate School Symposium Talk given at a conference Epigenetic memory in regeneration and cancer of Drosophila imaginal discs 10.06.2013 Berlin, Germany Paro Renato;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
BSSE_Novartis Workshop: Engineering Biomedicines – The Next Frontier Workshop 16.06.2015 Basel, Switzerland Paro Renato;
BSSE-Novartis Workshop: Engineering Biomedicines – The Next Frontier Workshop 14.01.2015 Basel, Switzerland Paro Renato;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions BSSE Open House Event German-speaking Switzerland 2015
Media relations: radio, television Das Erste Leben SRF1 German-speaking Switzerland 2015
Talks/events/exhibitions ETH Unterwegs German-speaking Switzerland 2015
Talks/events/exhibitions EPIGENETIK: Wie die Umwelt unser Erbgut prägt German-speaking Switzerland 2014

Associated projects

Number Title Start Funding scheme
164087 Lightsheet Microscopy 01.06.2016 R'EQUIP
160766 Immunologic consequences of time-graded exposure to an 'obesity-diabetes milieu' 01.08.2015 Sinergia

Abstract

Developmental decisions, defining lineage-specific expression patterns, need to be preserved during cell division. To this purpose, chromatin represents a major level of control Two groups of chromatin proteins are responsible for maintaining the differential gene expression patterns characterizing the individual cell types. The Polycomb group (PcG) proteins are required for a stable and heritable silencing of target genes. Conversely, the proteins of the Trithorax group (TrxG) counteract PcG repression and maintain the active expression state. Signals restricted in space and time initiate developmental choices, which are then subsequently maintained by the PcG/TrxG controlled chromatin functions. Hence, the interplay between these chromatin regulators utilizes epigenetic features and forms the molecular basis for the process of transcriptional memory. A major site of action for these epigenetic regulators is at promoters of target genes, in particular at promoters with a paused polymerase. PcG protein complexes place and bind histone modifications at repressed target genes, resulting in a reduced accessibility of the nucleosomal structure and in an inhibition of the transcriptional elongation process. The counteracting TrxG proteins exhibit functions, which open nucleosomal structures and allow the transcriptional machinery to enter processivity. Our understanding of transcriptional memory stems primarily from the involvement of the PcG and TrxG in maintaining developmental decisions. Here we would like to expand the view by analyzing whether environmentally induced stress conditions can impose epigenetically heritable gene expression states. We will used cellular systems inducible by environmental stimuli and combine new methodologies, like GRO-seq and PAR-CLIP, to study the dynamic behavior of PcG and TrxG proteins at target promoters and identify the crosstalk between the two groups at the transition from silenced to activated state. This will include the identification and functional analysis of non-coding RNAs found as important companions of PcG-induced repression. We will develop transgenic reporter systems in Drosophila sensing environmental cues and measure whether stress conditions can be imprinted into chromatin and epigenetically inherited through mitosis and meiosis.This project will provide mechanistic insight of how PcG and TrxG interactions faithfully maintain gene expression states. Given the broad spectrum of assignments this particular mechanism of transcriptional memory is executing, the knowledge gained on its role in memorizing environmental signals might even have implications for clinically relevant topics like susceptibility to late-onset diseases as diabetes or cancer.
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