Epigenome regulation by environmental factors to maintain stem cell integrity

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

The aim of this project is to identify how environmental factors, notably oxygen tension, affect self-renewal, differentiative plasticity and epigenomic integrity of stem cells.

Specifically, this question will be addressed in the context of trophoblast stem (TS) cells. TS cells are the progenitors of key placental cell types and represent the counterpart of embryonic stem (ES) cells. TS cells are of great scientific and potential clinical value. However, their plasticity may be affected by routine culture in ambient oxygen conditions while early development occurs in a low-oxygen environment. Oxygen tension may directly translate into epigenomic changes by regulating novel DNA methylation and demethylation pathways. This project will address the mechanistic aspects of how the epigenome is affected by this environmental effector, which may have important consequences on stem cell plasticity and regenerative capacity of TS cells. As such this project is at the forefront of epigenome regulation and stem cell biology with great relevance on related fields such as cancer epigenetics.

Publications

10 25 50
 
Description We have described developmental abnormalities that are observed in the offspring of aged mice, and shown a large proportion of these abnormalities can be linked to abnormal function of the placenta, rather than the oocyte. This research suggests that age-related changes in immune cell activity at the fetomaternal interface is unlikely to explain maternal-age-related abnormalities in embryonic development, however the transduction of hormonal signals in the aged mother may be altered, and may underlie diminished placental function. Further experiments suggest that maternal age may affect the uterine epigenetic landscape, and this may underlie altered hormonal signals in the aged mother.
Exploitation Route Further research following on from this grant may look to confirm conservation of our findings in aged mice to ageing in humans, and develop strategies to help older mothers to have healthy pregnancies. New treatments or drugs may be subsequently developed to combat this problem.
This research may provoke a change in the advice and/or treatment offered to older woman planning to have a baby, and to younger women who are planning to delay pregnancy until later in life.
Sectors Communities and Social Services/Policy,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description BSRA conference
Amount £340 (GBP)
Organisation Babraham Institute 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 07/2016
 
Title Young and aged mother uterus, uterine stromal cell, and conceptus samples 
Description A collection of samples of uterine tissue, uterine stromal cells, embryos, and placentas from young and aged mice. 
Type Of Material Biological samples 
Provided To Others? No  
Impact Production of next generation sequencing libraries from young and aged samples to analyse changes in gene expression and epigenetic marks with increasing age. 
 
Title Next generation sequencing libraries 
Description Next generation sequencing datasets describing transcriptomic and epigenetic changes that occur with age in mouse uteri and placenta. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Understanding of the functional changes that come about as a result of advanced age, during pregnancy in mice. 
 
Description Analysis of immune cells at fetomaternal interface in aged mice by FACS 
Organisation University of Cambridge
Department Department of Obstetrics & Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution Supply and dissection of placenta from pregnant mice.
Collaborator Contribution Isolation of immune cells from placenta, and processing of placenta for FACS analysis. Antibody staining of immune cells for lineage markers, and performing subsequent FACS experiment and data analysis.
Impact Data included in publication currently under review.
Start Year 2016
 
Description Analysis of uterine response to artificial in vivo decidualization in aged female mice 
Organisation National Institute of Environmental Health Sciences
Department Reproductive and Developmental Biology Laboratory
Country United States 
Sector Public 
PI Contribution Conception of biological question that advanced maternal age leads to uterine decidualization defects in mice. Generation of data leading to the genesis of this hypothesis. Generation and analysis of RNA-sequencing data to characterise aged uterine transcriptome.
Collaborator Contribution Design, expertise, and performance of artificial decidualization assay, supply of young and aged mice. Histology and immuohistochemical analysis of deciduoma tissues, supply of antibodies for this purpose. Sharing of previously generated microarray data to complement RNA-seq analysis generated by my team.
Impact Publication in Nature communications doi:10.1038/s41467-017-00308-x
Start Year 2016
 
Description 2nd year student talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact 10 minute presentation and questions to staff and students at the Babraham Institute.
Year(s) Of Engagement Activity 2016
 
Description BSRA conference poster & public engagement session 2016 Durham - LW 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Attended conference and presented poster
Year(s) Of Engagement Activity 2016
 
Description BSRA public engagement session 
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 Discussion workshop involving short presentations about ageing research, followed by informal conversations between researchers and the public about ageing, and ageing research.
Year(s) Of Engagement Activity 2016
 
Description Babraham Institute Athena Swan Committee member - SC 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Active participant of Athena Swan committee at the Babraham Institute
Year(s) Of Engagement Activity 2016,2017
 
Description Jeans for genes day careers talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I attended a local school on Jeans for genes day to give a presentation to an after school science club detailing my route from A level student to PhD student, and summary of my research. The talk led to questions about university applications and studying biology at undergraduate level, and discussion about epigenetics which the students had recently learnt about.
Year(s) Of Engagement Activity 2017
 
Description Royal Society Partnering Award - CS + LW, NM, SC 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Successful application for Royal Society Partnering Award. Poster 6 selected 6th form students over the course of 1 week and conducted in-depth research project. Data analysis followed at the pupils' school directly.
Year(s) Of Engagement Activity 2016,2017
 
Description Royal Society schools partnership 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 6 secondary school pupils and their teacher undertook a project looking at transcriptional changes that occur as a result of X inactivation. The project sparked discussion about next generation sequencing techniques, and how this phenomenon can be observed in the real world. Students presented this project and a poster at The Royal Society.
Year(s) Of Engagement Activity 2017
 
Description School's Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact provided basic explanation of early development and the importance of the placenta for growth of a baby; hands-on experience for students in staining and microscopic analysis of a mouse placenta

rose awareness of research activities and importance of basic research to understand common pregnancy-associated diseases
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
 
Description Schools Day 
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 Schools
Results and Impact Project design, scientific background induction and practical supervision for 6th form students as well as teachers during Annual Schools Day.
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Schools day 
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 Small groups of students and teachers visited the institute, and participated in half day workshops learning about the science done in that lab, and performing relevant short experiments to introduce them to relevant techniques and experiences. Schools reported pupils and teachers enjoyed the activities, pupils reported to us that they wanted to pursue careers in science, and had conversations with lab members on how to do this.
Year(s) Of Engagement Activity 2016,2017,2018