Genomic imprinting and the epigenetic control of developmental processes

A large number of serious diseases, including type2 diabetes and cancer, are caused by a combination of our genetic make-up (our DNA) and environmental influences. We believe that our DNA can be directly influenced by the environment in which it finds itself. Sometimes the effect of the environment is part of normal change that a cell goes through. In particular we study how the environment influences how DNA is normally packaged into chromosome inside the cell. This process of DNA packaging is not haphazard but highly regulated and is different between young cells and old cells, brain cells and muscle cells.

Understanding how the environment signals to cells and causes them to become abnormal is a difficult problem to address. One way to do this is to study a system where cells normally have to respond to their environment and change their behavior. A good system to investigate in this is through the study of cells known as stem cells, that are changing in the normal process of developing into body parts such as the brain, fat or muscles. These developing cells are good models because these are the types of cells that can go wrong in cancer so results generated from studying them in normal development can be compared with results generated when they are behaving abnormally.

Here we will study the relationship between the DNA and the regulatory processes that package it into chromosomes while stem cells are developing. We will learn how this affects the behavior of genes encoded by the DNA and what happens to these genes in different cell types and in different environments.

Genomic imprinting is an epigenetically regulated process causing genes to be expressed according to their parental origin. Genetics studies have shown that genomic imprinting occurs at dosage-sensitive genes and regulates important developmental processes during the lifetime of the mammal. In human, altered imprinted gene expression is associated with growth, metabolic and neurological disorders, and cancer.

Imprinting is regulated by DNA methylation, an epigenetic modification that differentially marks the two parental chromosomes influencing long range cis-acting control of the activity and repression of protein-coding and small and large regulatory non-coding RNAs. Over the past 20 years, genomic imprinting has emerged as a useful paradigm contributing to our understanding of the roles of epigenetic modifications in the regulation of gene activity and repression, and into wider mechanisms underlying the epigenetic control of genome function in development, health and disease.

Recently we have shown in a developmental model of postnatal neurogenesis, selective absence of imprinting occurs to control gene dosage in the stem cell niche and this is required to maintain the postnatal stem cell pool and the synthesis of new neurons. This suggests that dosage control by imprinting may be an epigenetically modulatable process that can adapt to particular environmental requirements during development. Understanding epigenetic modulation in response to environmental signals is a major challenge in biomedical research. The proposed research aims to focus on mechanisms and developmental pathways associated with this.

Addressing these aims has timely general implications for understanding the epigenetic regulation of the stem cell niche and for the characterization of factors and pathways that influence the relationship between stem cells and their environment contributing to our understanding of adult onset diseases, neuronal plasticity, aging and cancer.

The research is of impact to the basic scientific community, the biomedical community and fall within the strategic research priority areas of the MRC including epigenetics, environmental influences on health and disease and stem cell biology. The work has a primary focus that uses animal genetic models and in vivo analysis hence studies the impact of the research on the whole organism with direct application to human health and disease.

The applicant is regularly asked to provide information to the press and media about her own work, the related work of others and to comment on the wider implications of epigenetics, environment and disease and its relation to society and the public at large. In the past this has included comments and interviews for the Times, the NY Times, BBC Radio 4, Science News, GenomeWeb daily news, and next week she will talk to a BBC Radio 4 reporter on nutrition, the environment and implications for human health. In order to increase the quality of these communications, earlier this year she participated in a one-on-one training workshop organized by the MRC press office, receiving formal training on being interviewed by newspaper, TV and radio journalists. In 2009 she was a specialist advisor at the House of Lords Enquiry into Genomic Medicine. She co-founded the UK International Human Epigenome Network culminating in the MRC becoming a founder partner of the worldwide International Human Epigenome Consortium which will oversee international efforts to sequence reference epigenomes and integrate them into genome-wide databases, disseminate data and facilitate quality measures and consistency amongst these projects. In the past five years she has co-organized six international conferences and has lectured to school children from the UK and abroad on DNA, and on past and present research at the University of Cambridge. In the past three years has presented her team's research at over 70 national and international symposia and lectures. Her current research team consists of 17 scientists who are encouraged to attend scientific meetings and disseminate their results, develop collaborations and discuss progress and state of the art in the field.

She is a member of two European Consortia (BLUEPRINT and EpiGeneSys) involved in disseminating, sharing and networking which provides an additional forum for dissemination, collaboration and the exchange of ideas. She sits on the editorial boards of four journal - Nature Communication, Reproduction, PLoS Genetics (Section Editor - Epigenetics) and Epigenetics and Chromatin hence is aware of current developments in the field. She is committed to open access publishing, and where appropriate published in open access journals. She is a member of the Genetics Society, British Society for Develomental Biology and the Anatomical Society of Great Britain and Ireland. She is an elected member of EMBO and is on the panel scrutinizing and awarding prestigious Young Investigator Award Grants.

The applicant has contacts with Cambridge Enterprise that focuses on the exploitation of results for the public benefit. She has funding from the Technology Strategy Board with the goal of generating stem cells tools for the scientific community. She regularly has contact with representatives from Cambridge Enterprise and also interacts with companies looking to exploit her research such as Sigma, Cellcentric and Cellzome. She sits on the Scientific Advisory Board of Cellzome hence is aware of current opportunities to exploit epigenetics research. She also sits on the Scientific Advisory Boards of CAiTE (University of Bristol) and CGAT (University of Oxford).