Reprogramming and Chromatin

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

There are hundreds of cell types in an 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 numbers of epigenetic marks (DNA and chromatin modifications) are added on genes in order to restrict the developmental potential of each cell.||In order to change this cell fate, all the epigenetic information needs to be erased and re-set. Such process (epigenetic reprogramming) normally occurs during embryonic development (at the onset of the development in one cell embryo; and later on - in early embryonic germ cells). Additionally, such process underlies regeneration and aberrant reversal of cell fate observed in cancer. Similar 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 lab is to unravel mechanisms underlying the natural reprogramming events that occur in mouse zygote and germ cells. Investigation of the mechanisms operating during these processes can add to our understanding of 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 very efficiently in the course of embryonic development. Detailed understanding of these processes can add to our ability to efficiently reprogramme cells in vitro.||Our lab uses mouse zygotes and developing germ line (primordial germ cells PGCs) as in vivo models where epigenetic reprogramming occurs naturally in vivo. The germ line carries unique epigenetic properties, since the reprogramming process involves both genome wide DNA demethylation (including erasure of genomic imprints) and chromatin remodelling. In comparison, the reprogramming process in zygotes involves genome wide DNA demethylation that affects only the paternal genome a few hours after fertilisation.||In order to decipher molecular mechanisms underlying the reprogramming processes we concentrate on 2 main areas:||1) Mechanisms underlying DNA demethylation and erasure of genomic imprints|We have previously documented the kinetics of erasure of DNA methylation and genomic imprints during the development of mouse primordial germ cells (Hajkova et al, 2002, Hajkova et al 2008). Based on the kinetics of the process we suggested that DNA demethylation driven through DNA repair pathway is the most likely scenario to operate in germ cells. We are currently testing this hypothesis.||2) Interplay between DNA demethylation and chromatin dynamics ||Besides our efforts to decipher the mechanisms responsible for large scale loss of DNA methylation in germ cells and zygotes, we are particularly interested in the cross-talk and regulation between DNA demethylation and large scale chromatin remodelling.

Publications


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Hajkova P (2010) Epigenetic reprogramming--taking a lesson from the embryo. in Current opinion in cell biology
Hajkova P (2011) Epigenetic reprogramming in the germline: towards the ground state of the epigenome. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Hajkova P (2011) Epigenetic reprogramming in the germline: towards the ground state of the epigenome. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Hajkova P (2010) Epigenetic reprogramming--taking a lesson from the embryo. in Current opinion in cell biology
 
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 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)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 03/2013 
End 09/2015
 
Description FP7 Marie Curie postdoctoral fellowship
Amount £176,655 (GBP)
Organisation Marie 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 of America
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 of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 03/2016
 
Description Marie Curie Incoming Postdoctoral Fellowship
Amount £178,000 (GBP)
Organisation Marie 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 of Great Britain & Northern Ireland (UK)
Start 03/2016 
End 03/2016
 
Description Strategic Alliance PhD Scholarship
Amount £101,756 (GBP)
Organisation Government of Taiwan 
Sector Public
Country Taiwan
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 of America 
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 manuscript in preparation
Start Year 2014
 
Description EMBO short term fellowship 
Organisation Institute of Genetics and Molecular and Cellular Biology (IGBMC)
Country France, French Republic 
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
Start Year 2013
 
Description EpigeneSys 
Organisation University of Sheffield
Department epiGenesys Ltd
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution mapping DNA modifications in the germ line (in progress)
Collaborator Contribution funding, annual meetings
Impact in progress
Start Year 2011