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Transcription factor dynamics in hematopoietic cell fate control

English title Transcription factor dynamics in hematopoietic cell fate control
Applicant Schroeder Timm
Number 156431
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 Cellular Biology, Cytology
Start/End 01.06.2015 - 31.05.2018
Approved amount 550'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Molecular Biology

Keywords (7)

Stem cell; Differentiation; Imaging; Transcription factor; Dynamics; Signaling; Hematopoiesis

Lay Summary (German)

Lead
Netzwerke von Transkriptionsfaktoren steuern das Verhalten aller Zellen des Blutsystems. Ihre eigene Regulation ist bisher jedoch schlecht verstanden. Das Projekt quantifiziert die Expression verschiedener Transkriptionsfaktoren in Stamm- und Vorläuferzellen des Blutsystems kontinuierlich über lange Zeiträume auf Einzelzellebene.
Lay summary

Unser Blutsystem produziert in jeder Sekunde des Lebens Millionen der richtigen Art neuer Blutzellen. Transkriptionsfaktoren steuern genetische Programme in Zellen. Sie kontrollieren das Verhalten aller Zellen des blutbildenden Systems. Zwar kennt man inzwischen viele Transkriptionsfaktoren die eine wichtige Rolle bei der Steuerung bestimmter Zelltypen spielen. Wie genau diese Transkriptionsfaktoren, welche zu komplexen Netzwerken zusammengeschaltet sind, in einzelnen Zellen reguliert sind ist jedoch schlecht verstanden. Insbesondere gibt es bislang keine Daten zur dynamischen Expression von Transkriptionsfaktoren in individuellen Zellen über die Zeit.

Das Projekt verwendet eine Kombination aus neuartigen Mikroskopieverfahren, molekularbiologischer Methoden, Softwareentwicklung und Ingenieursmethoden um die Expressionsdynamik verschiedener Transkriptionsfaktoren in einzelnen lebenden Zellen des Blutsystems über viele Tage zu quantifizieren. Diese Daten werden es erlauben besser zu verstehen wie Transkriptionsfaktoren zu Netzwerken zusammengeschaltet sind, wie diese Netzwerke reguliert sind, und wie dies die Differenzierung einzelner Stamm- und Vorläuferzellen des blutbildenden Systems kontrolliert.

Das Projekt befasst sich mit Grundlagenforschung. Das Ziel ist eine Quantifizierung der Dynamik von Transkriptionsfaktoren in blutbildenden Zellen. Dies ist notwendig um die molekulare Steuerung des gesunden Blutsystems, und die Ursachen hämatologischer Erkrankungen wie z.B. Leukämien, besser verstehen und klinisch beeinflussen zu können.

Direct link to Lay Summary Last update: 20.05.2015

Responsible applicant and co-applicants

Employees

Publications

Collaboration

Group / person Country
Types of collaboration
Fabian Theis Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Claus Nerlov Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Co-organizer, Wellcome Trust series conference "Single Cell Biology” in Hinxton, UK 14.03.2018 Hinxton, Great Britain and Northern Ireland
President of the ISEH, Annual ISEH meeting 23.08.2017 Frankfurt, Germany
Co-organizer, ISSCR International Symposium 2017 ‘Translational Opportunities in Stem Cell Research’ 09.02.2017 Basel, Switzerland
Head of Scientific Program Committee, Annual ISEH meeting 23.08.2016 San Diego, United States of America
Co-organizer, Wellcome Trust series conference "Single Cell Biology” 08.03.2016 Hinxton, Great Britain and Northern Ireland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Lecture at Scientifica 2017 German-speaking Switzerland 2017

Awards

Title Year
Bruno Speck Award 2017, Stiftung für Hämatologische Forschung Basel, Switzerland 2017
Erwin Schrödinger Prize - The Stifterverband Science Award 2017 German national award for interdisciplinary research Shared with Prof. Theis & Dr. Marr (Munich, Germany) and Dr. Haghverdi (Cambridge, UK) 2017

Associated projects

Number Title Start Funding scheme
179490 Molecular dynamics in hematopoietic stem and progenitor cell fate control 01.06.2018 Project funding (Div. I-III)
177079 Confocal Microscope with spectral detection, FLIM and laser ablation 01.12.2017 R'EQUIP
179490 Molecular dynamics in hematopoietic stem and progenitor cell fate control 01.06.2018 Project funding (Div. I-III)

Abstract

Despite the importance of hematopoietic stem and progenitor cells (HSPCs), their molecular control remains poorly understood. The central role of transcription factors (TFs) and their networks (TFNs) in controlling HSPC fates in well recognized. However, it is unclear how the TF expression in their TFNs is regulated and how precise integration of cytokine signaling with the TFN controls HSPC fate decisions. One major reason is that complex HSPC differentiation systems are usually analyzed at only the population level and / or only at individual time points. However, for a comprehensive understanding of molecular cell fate control, both cell behavior and molecular expression or activity have to be quantified at the single cell level and continuously over many days. We have developed novel bioimaging systems allowing the continuous long-term quantification of cell behavior and protein expression or activity in individual differentiating cells. We will use these approaches to quantify, continuously and at the single cell level, cellular behavior, TF expression and cytokine signaling activity during HSPC differentiation. In combination with inducible molecular manipulation of TF expression and signaling activity, this novel kind of data will be used to generate improved models of HSPC fate control. In addition to analyzing existing TF reporter lines, we will generate novel reporter mouse lines to extend current analyses to other TFs. Novel microfluidic devices will be designed and produced to allow the high throughput combinatorial manipulation of culture conditions during long term time-lapse of HSPC cultures. From the novel kind of long-term single cell quantification, we expect much improved insights into the regulation and role of signaling pathways and TFN regulation in controlling HSPC fates.
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