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.
People |
ORCID iD |
Publications

Amouroux R
(2016)
De novo DNA methylation drives 5hmC accumulation in mouse zygotes.
in Nature cell biology

Benešová M
(2017)
Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation.
in Molecular carcinogenesis

Carrillo-Jimenez A
(2019)
TET2 regulates the neuroinflammatory response in microglia



Cvetesic N
(2018)
SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA.
in Genome research



Dukatz M
(2019)
Mechanistic Insights into Cytosine-N3 Methylation by DNA Methyltransferase DNMT3A.
in Journal of molecular biology

Eguizabal C
(2016)
Characterization of the Epigenetic Changes During Human Gonadal Primordial Germ Cells Reprogramming.
in Stem cells (Dayton, Ohio)
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 | Charity/Non Profit |
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 | Public |
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 | Charity/Non Profit |
Country | Global |
Start | 09/2013 |
End | 09/2015 |
Description | Proximity to Discovery |
Amount | £13,700 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 |