Reprogramming and Chromatin

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

There are hundreds of cell types in adult organism. Despite the fact that these cells have different functions, they all contain the same genetic material. The destiny of each cell in the body is set through a series of cell fate decisions that occur early in embryonic development. During this process numerous epigenetic marks (DNA and chromatin modifications) are added on genes in order to allow or permanently prevent their activation; this effectively leads to the restriction of the developmental potential of each cell. Consequently, in order to change the resulting cell fate, all the acquired epigenetic information needs to be erased and re-set. Such process (epigenetic reprogramming) normally occurs during embryonic development (at the onset of embryonic development in one cell embryo; and later on - in early embryonic germ cells). Additionally, similar process underlies regeneration and aberrant reversal of stable cell fate observed in cancer. Reprogramming processes can also be artificially induced in vitro, whereupon a somatic differentiated cell is changed to resemble cells of early embryos. Efficiency of this is, however, very low due to our lack of understanding of molecular mechanisms involved. The aim of our research is to unravel mechanisms underlying the natural reprogramming events that occur in mouse early embryos and germ cells. Investigation of the mechanisms operating during these processes will help us to understand regeneration and cancer and significantly improve our ability to manipulate cell fate in vitro.

Technical Summary

The process of epigenetic reprogramming requires global resetting of epigenetic memory at the level of DNA methylation and chromatin modifications. This process leads to major shifts in gene expression profile and can lead to a change in cell fate.
In mammals, under physiological conditions epigenetic reprogramming occurs in the course of development and potentially to some extent also as a part of the regenerative processes during wound healing. Aberrantly, similar processes that reverse cell fate decisions might be partially recapitulated during cellular dedifferentiation observed in cancer. In vitro, several reprogramming systems have been described that could be used to revert somatic cell phenotype and to regenerate pluripotency: somatic cell nuclear transfer (SCNT), generation of induced pluripotent cells (iPS), cell fusion or permeabilisation of cells followed by incubation with protein extracts - amongst others. However, these in vitro reprogramming systems are very inefficient, show high degree of variability, and often generate cells with intermediate phenotypes.
In order to gain deep mechanistic insights into the molecular processes underlying epigenetic reprogramming we decided to focus on the naturally occurring reprogramming that operates efficiently in the course of embryonic development. |Our laboratory uses mouse zygotes and developing germ line (primordial germ cells, PGCs) as models where epigenetic reprogramming occurs naturally in vivo. In order to decipher molecular mechanisms underlying these reprogramming processes we concentrate on 2 main areas:1) Mechanisms underlying DNA demethylation and erasure of genomic imprints. |2) Interplay between DNA demethylation and chromatin dynamics
Detailed understanding of the naturally occurring reprogramming processes will add to our ability to efficiently reprogram cells in vitro.

Publications

10 25 50
 
Description ESHRE Expert Meeting on the "Epigenome and the Human Embryo in Vitro
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description Lecturing during the ESHRE campus ion germ cells n Bilbao
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact The ESHRE campuses/workshops inform the colleagues working in the field of reproductive medicine about the newest breakthroughs in relevant reserach areas (gamete development, reprogramming, epigenetics...). This knowledge transfer has a direct impact on changes implemented in the reproductive medicine and assisted reproduction technologies fields.
 
Description participant in the ESHRE SISMER annual meeting (Bologna 2011)
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description teaching in the ESHRE accrediation course :ESHRE Annual meeting Munich 2014
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description teaching in the ESHRE accrediation course :ESHRE campus Lisbon 2010
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description teaching in the ESHRE accrediation course :ESHRE campus Lisbon 2014
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description teaching in the ESHRE accrediation course :ESHRE campus London 2012
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description teaching in the ESHRE accrediation course :ESHRE campus London 2013
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description teaching in the ESHRE accrediation course :ESHRE campus: Cryopreservation, IVF in the frozen state (Istanbul 2015)
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description EpigeneSys RISEI
Amount € 150,000 (EUR)
Funding ID 257082 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 03/2013 
End 09/2015
 
Description FP7 Marie Curie postdoctoral fellowship
Amount £176,655 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 03/2011 
End 03/2013
 
Description Keystone travel fellowship
Amount £755 (GBP)
Organisation Keystone Symposia on Molecular and Cellular Biology 
Sector Charity/Non Profit
Country United States
Start 02/2012 
End 02/2012
 
Description MRC Doctoral Prize
Amount £26,931 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 03/2016
 
Description Marie Curie Incoming Postdoctoral Fellowship
Amount £178,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 09/2013 
End 09/2015
 
Description Proximity to Discovery
Amount £13,700 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 03/2016
 
Description Strategic Alliance PhD Scholarship
Amount £101,756 (GBP)
Organisation Government of Taiwan 
Sector Public
Country Taiwan, Province of China
Start 10/2012 
End 09/2015
 
Description Collaboration with New England Biolabs on development of new methods to map DNA modifications in minute biological samples 
Organisation New England Biolabs
Country United States 
Sector Private 
PI Contribution providing biological material and relevant genetic model/system to test new methods on
Collaborator Contribution development of new methods provision of chemicals/reagents for the experiments
Impact Hill et al, Nature 2018
Start Year 2014
 
Description EMBO short term fellowship 
Organisation Institute of Genetics and Molecular and Cellular Biology (IGBMC)
Country France 
Sector Academic/University 
PI Contribution our team is providing expertise in germ line development
Collaborator Contribution the co-operating lab is providing mouse trasgenic models
Impact award of EMBO short term fellowship for a postdoctoral fellow's visit to our laboratory , this work resulted in a joint publication Izzo et al, JCB 2017
Start Year 2013
 
Description EpigeneSys 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution mapping DNA modifications in the germ line
Collaborator Contribution funding, annual meetings
Impact publications Amouroux et al, Nat Cell Biology 2016, Hill et al, Nature 2018
Start Year 2011
 
Title Gametogenesis 
Description The present invention relates to methods of inducing gametogenesis in vitro. Reagents and kits for use in the methods of the invention are also provided. The present invention finds use in the field of medicine, particularly in the study and treatment of infertility. 
IP Reference GB1721724.1 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact patent application submitted to protect the finding