Genomic imprinting and the epigenetic control of developmental processes

All the cells in our body are genetically identical and contain 46 chromosomes (23 pairs) where all of our genes are located - 23 chromosomes originally came from our mother's egg and 23 from our father's sperm. Thus, since the time of conception, a normal individual will have two copies of every gene.

This application is about a process called Genomic Imprinting. Imprinting causes specific genes to be turned on (expressed) solely from the maternal or from the paternal copy rather than from both copies. It is a process that affects only about 1% of our genes. But control of gene dosage by imprinting is important during development, and when imprinting goes wrong this leads to growth defects, neurological syndromes and cancer. This grant explores the regulation, function and evolution of imprinting, so we can understand these disease processes better.

We are interested in understanding mechanisms of imprinted expression. What makes an imprinted gene be expressed from one of the chromosomes in a pair rather than both of them? The process causing only the paternally inherited or the maternally inherited copy to be expressed, is an 'epigenetic' one. Epigenetics means 'on top of genetics' and the epigenetic state at an imprinted gene is manifested as chemical modifications that sit on the DNA at only one parental chromosome and not the other causing the gene located there to be expressed on one of the chromosomes and kept off on the other.

Our first aim is designed to ask whether all imprinted genes are fully ON on one chromosome and fully OFF on the other, or whether some imprinted genes are expressed from both chromosomes but more from one chromosome and less from the other. This is important for understanding mechanisms of imprinting and whether more genes are imprinted than originally thought. This has implications for disease.

In our second aim, we are interested in focusing on the function of a particularly important imprinted gene (Dlk1) that is able to act not only in an imprinted way, but also be expressed like other genes from both parental chromosomes. This is a remarkable gene whose dosage is very important in the brain and elsewhere in the body too. In fact, it also regulates the development of our fat, and controls metabolism. Interestingly there is another gene that looks very like this one (Dlk2); it is never imprinted and is the ancestor to Dlk1 which arose as a copy of Dlk2. Dlk2 only functions in the brain. In this set of experiments, we will study the relationship between these two genes, asking how and why one evolved from the other, why one is imprinted and the other not, and the extent to which they act in the same and in different pathways.

Genes regulated by imprinting are very important for controlling growth and development in the womb and this has been extensively studied in the placenta which is an essential site of imprinted gene expression. However, since important nutritional events happen after birth too, we hypothesize that imprinted genes also regulate postnatal nutrition. In our third aim, we will ask whether the ability to feed milk to offspring via the mammary gland is also controlled by genomic imprinting. Since the mammary gland undergoes dramatic changes during pregnancy, lactation and upon weaning, it is likely that these changes are subject to epigenetic control. Hence the experiments outlined in this third aim will not only provide important knowledge about the development of the mammary gland and the exchange of nutritional resources between mother and baby, but might also provide useful insights into our understanding of the function, mechanism and evolution of the imprinting process.

Genomic imprinting is a mammalian epigenetically regulated process causing genes to be expressed mono-allelically according to their parental origin. Genetic studies have shown that genomic imprinting occurs at dosage-sensitive genes regulating important developmental processes. In human, altered imprinted gene expression is associated with growth, metabolic and neurological disorders, and cancer. Over the past 30 years, genomic imprinting has emerged as a paradigm contributing to our understanding of the roles of epigenetic modifications in the regulation of gene activity and repression, and to mechanisms underlying the epigenetic control of genome function in pathways important for development, health and disease.

In this application we propose a series of experiments addressing three key important biomedically relevant topics concerning the regulation, function and evolution of genomic imprinting. These studies are designed not only to better understand imprinting in development and disease, but also to generate more widespread functional and regulatory insights into the epigenetic control of transcriptional dosage, and its impact on normal and abnormal phenotypes.

Our three main aims are:
1 - To understand the extent and implications of parental-origin specific allelic bias.

2 - To further study one of the most biomedically relevant imprinted genes, Dlk1, and the previously uncharacterised non-imprinted Dlk2 gene from whence it arose, to assess the regulation, function and evolution of these remarkable paralogues in mammals using neurogenesis as a paradigm.

3 - To determine whether canonical imprinting, an essential mammalian regulator of nutritional resources, plays a role in the mammary gland - a key site of postnatal maternal-offspring interactions important for lifelong offspring health.

1. Biomedical, academic and societal impact
Our research falls into the category of discovery science. The results will have an impact on our understanding of the regulatory components associated with the cycling of the mammary gland, the regulation of materno-fetal postnatal resource control, and for the healthy development and subsequent adult well-being of mammalian offspring. This project to study imprinting in lactation and the postnatal allocation of resources by mother to her baby, fits with a strategic priority of the MRC to encourage research that will increase mechanistic understanding of early nutrition and its relation to life-long health. It will benefit society through better understanding of the mechanisms allowing healthy breast-feeding. Understanding the molecular basis of neurogenesis and the ability to activate stem cells in the adult brain to generate new neurons has important implications for our understanding of neural regeneration and neural functions especially in adult and ageing populations. Our research will benefit academics as outlined in the section on Academic Beneficiaries.

2. Educational impact
Our research team is composed of both 'wet' and 'dry' researchers, with individuals either switching between the two modes as required, or interacting collaboratively with each other in joint projects. This provides a valuable inter-disciplinary context encouraging communication and understanding between individuals with different research backgrounds. The group has a long track-record in training postdoctoral researchers, undergraduates and graduate students, from within and outside the UK. For this project, we will create an environment where students and postdocs can be trained in a range of technologies and ways of working: mouse phenotypic analysis, cell culture experiments, imaging analysis, developmental biology and bioinformatics analysis. Furthermore, every year during the course of the project, we will offer a 3-month project for three undergraduate Genetics students. Not only will we teach them contemporary techniques, but we will also tutor them more broadly to develop independently as scientists, and help them learn to critically evaulate both their own and the work of others and to articulate this in a constructive manner. In addition, we accept summer trainees, work experience students and other students from abroad. On average, the lab trains 9 visitors/visiting students per year - mostly junior trainees. During the course of this project, such individuals will become familiar with research using animal models, biochemical approaches to functional genomics and genome-wide datasets. We know from past experience that the opportunities we provide these young beneficiaries, has an impact on their career development and the science they conduct in the future.