Epigenetic and Signal Transduction Interactions in Development and Stem Cell Differentiation

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

During early mammalian development, the embryo undergoes an important transition where cells become specialised and are orientated to be the building blocks of the future body. How this process is controlled remains poorly understood but it is important to study because it will provide insight in to how distinct cell types are formed in the embryo. Scientists are trying to mimic these events in order to control specialisation of stem cells. By better understanding how this process occurs, we may uncover new ways to turn stem cells into useful cell types, such as heart and liver, that we can use for cell-replacement therapies. I have chosen to study a protein called Ezh2, which regulates what genes are turned on and off, because we know that it has an essential role during this transition in mouse development. By studying mouse embryos at a very early stage in development, together with stem cells in culture, I will uncover how Ezh2 is involved in this process and also what are the signals that control Ezh2 itself.The first objective of this research is to identify the genes that Ezh2 is regulating during stem cell specialisation and also find out how Ezh2 is recruited to these particular sites in the genome. The second objective is to examine what happens to this set of genes when we genetically remove Ezh2 from the stem cells and also from the embryo – the prediction being that they will fail to be regulated properly and this should tell us exactly why Ezh2 is essential for this early stage of development. The third objective is to identify the signals that control the activity and recruitment of Ezh2 during stem cell specialisation, and this should explain how Ezh2 regulation is linked to other important processes that occur during development. This research will identify why Ezh2 is essential for the specialisation of cells during development. Understanding the detailed mechanisms of how this process occurs may lead to improved control over stem cells and our ability to use them for therapy. Ezh2 also has important roles outside of development, especially in the early stages of cancer where the normal process of regulating Ezh2 is lost. By better understanding how Ezh2 is controlled, we may identify new ways to detect this early warning sign and also to prevent this alteration from occurring.

Publications

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Houseley J (2015) Annual meeting of the EpiGeneSys Network of Excellence--Advancing epigenetics towards systems biology. in BioEssays : news and reviews in molecular, cellular and developmental biology

 
Description The overall aim of the work was to investigate how epigenetic processes (such as the Polycomb-group protein Ezh2) integrate with signalling proteins and transcription factors to coordinate gene regulatory programmes in development and stem cell differentiation. We have uncovered important new mechanisms that drive extensive and coordinated changes in the epigenome during the early stages of development and stem cell differentiation: 1) we found that pluripotency transcription factors provide a direct connection between cell-state and chromatin organisation through modulation of heterochromatin regions in embryonic stem cells (Novo et al., Genes & Development 2016; Novo et al., Cell Reports 2018); 2) We have also discovered a human-specific, X-chromosome pre-inactivation state, which is defined by the co-expression of two opposing long, non-coding, RNAs XIST and XACT, and this pattern is tightly linked to pluripotent state in human embryos and stem cell lines (Vallot et al., Cell Stem Cell 2016); 3) We have discovered new insights into the epigenetic changes and functions during the transition between naïve and primed human pluripotent states (von Meyenn et al., Developmental Cell 2016; Collier et al., Cell Stem Cell 2017); 4) We have characterised the first EZH2-deficient human pluripotent stem cells and found there is a broad conservation of Polycomb-group protein function in controlling cell-fate decisions and transcriptional programs during early human development (Collinson et al., Cell Reports 2016). We also uncovered unexpected human-specific differences that result in a more severe self-renewal and proliferation phenotype than that of PRC2-deficient mouse ESCs. Polycomb-mediated H3K27me3 also impacts enhancer priming in human pluripotent stem cells. 5) We have used Promoter Capture Hi-C together with newly developed computational approaches to identify new insights into how cis-regulatory inputs coordinate gene transcription upon cell differentiation (Freire-Pritchett et al., eLife 2017). Together, these studies provide new concepts and new technologies for understanding how epigenetic processes work together to impact developmental and stem cell regulation, particularly in humans.
Exploitation Route We have generated several genome wide data sets (gene expression; chromatin profiling), which we have made fully available to other researchers. We have also worked with several companies to build on the knowledge output from this grant, for example in developing new tools to isolate human pluripotent states.
Sectors Healthcare

 
Description We have contributed to the economic competitiveness of the UK by working with several companies to take forward our research, particularly in the sectors of stem cell biology, reagent development and supply, and regenerative medicine. As an example, this has led to a PhD student co-supervised by a company and myself. We have increased the effectiveness of public policy by contributing to several policy discussions and workshops, particularly in the area of gene editing and human embryology. This also includes a POSTnote on gene editing.
First Year Of Impact 2015
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic,Policy & public services

 
Description Contribution to POSTnote on genome editing
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://researchbriefings.parliament.uk/ResearchBriefing/Summary/POST-PN-0541
 
Description Gene editing policy
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description MRC CASE
Amount £112,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 10/2020
 
Description RISE1 membership of the EU Network of Excellence EpiGeneSys
Amount € 150,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2013 
End 09/2015
 
Title Identification of cell-surface proteins that can distinguish between human pluripotent states 
Description We have developed a new method to identify and flow-sort human naive and primed pluripotent stem cells based on their different cell-surface protein expression. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact We have published our method (Cell Stem Cell, 2017) and we anticipate other researchers to use the method in their own research. 
 
Title Cell Stem Cell 2017 
Description We have deposited RNA-sequencing data related to our publication in Cell Stem Cell, 2017. The data have been uploaded to GEO under accession number GSE93241. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The data relate to the reprogramming of human pluripotent stem cells. We anticipate that these data will be used by other researchers. 
 
Title eLife 2017 
Description High-through sequencing data related to our 2017 published in eLife. Data deposited in GEO under accession number GSE86821 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact We provide the coordinates for promoter-enhancer interactions in human pluripotent cells and differentiated cells. The data will be re-used by other researchers. Too early for measured impacts. 
 
Description Claire Rougeulle 
Organisation Paris Diderot University
Country France 
Sector Academic/University 
PI Contribution We have provided cell lines and contributed experiments to an ongoing collaboration.
Collaborator Contribution Our collaborators have made key discoveries about X-chromosome inactivation in human cells.
Impact Manuscript in preparation.
Start Year 2015
 
Description David Bazett-Jones 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution We have collaborated with David Bazett-Jones to examine the nuclear organisation in various cell types, including embryonic stem cells. For this collaboration, we have provided David with several cell samples.
Collaborator Contribution David has used a technique called electron spectroscopic imaging to investigate nuclear organisation in the cell samples that we have provided.
Impact The output of this collaboration is new knowledge about the nuclear organisation in embryonic stem cells and various mutant lines.
Start Year 2011
 
Description Fredrik Lanner 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution We have made new discoveries about human pluripotent states.
Collaborator Contribution Our collaborators have shared data, provided reagents, and participated in a shared project with us.
Impact None
Start Year 2015
 
Description Guiseppe Lupo 
Organisation Sapienza University of Rome
Country Italy 
Sector Academic/University 
PI Contribution We have profiled the epigenome and transcriptome of aged neural stem cells. We have also hosted GL in our laboratory over two summers and provided training in epigenomics techniques.
Collaborator Contribution Our partners derived and characterised young and aged neural stem cells, provide expertise in neural biology, and have given training to us in neural stem cell cultures.
Impact Manuscript in preparation.
Start Year 2014
 
Description Ian Chambers 
Organisation University of Edinburgh
Department MRC Centre for Regenerative Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have identified a new role for the transcription factor Nanog in regulating heterochromatin in mouse embryonic stem cells.
Collaborator Contribution Our collaborators have provided key cell lines, gel shift assays and expertise to the project.
Impact Paper in revision.
Start Year 2014
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Exhibit about Babraham's research at Cambridge Science Festival
Year(s) Of Engagement Activity 2015
 
Description DNA extraction from fruit Babraham Campus visit from Home educated children 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Extract DNA from fruit whilst showing how to "be a scientist" to home schooled children.
Impact: hands on activity to explain the basics of DNA and promote a career in research to home schooled children.
Year(s) Of Engagement Activity 2016
 
Description Epigenetics lecture for Monday Biology Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Lecture to introduce the basics and the importance of Epigenetics to Biology GSCE and A-level students.
Impact: improve students' understanding of Epigenetics; promote career in research.
Year(s) Of Engagement Activity 2016
 
Description Epigenetics lecture for Teacher Twilight Session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact An after-work lecture to introduce the basics and the importance of Epigenetics to Biology teachers.
Impact: prepare teachers into Epigenetics, a subject recently introduced to the curriculae.
Year(s) Of Engagement Activity 2016
 
Description Royal Society 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Our exhibition enabled a two way dialogue with the public about what we do and why it is important.

I was invited to write an article for "Chemistry and Industry" magazine about our research, which was published in 2012.
Year(s) Of Engagement Activity 2012
 
Description Short talk to LIYSF students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Short introduction on our research (epigenetics and nuclear organization) to students attending London International Youth Students Forum (LIYSF).
Impact: introduce students to Epigenetics and promote of scientific career.
Year(s) Of Engagement Activity 2016