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A human genome-wide screen for transgenerational epigenetic inheritance

Reference	BB/H012494/1
Principal Investigator / Supervisor	Dr Vardhman Rakyan
Co-Investigators / Co-Supervisors	Professor Richard David Graham Leslie
Institution	Queen Mary University of London
Department	Sch of Medicine & Dentistry
Funding type	Research
Value (£)	280,082
Status	Completed
Type	Research Grant
Start date	19/04/2010
End date	14/02/2013
Duration	34 months

Abstract

In recent years, several studies have reported inter-individual phenotypic differences that cannot be explained by genetic or environmental heterogeneity, and yet are transmitted to the offspring. We are now beginning to realize that the molecular mechanisms at the heart of these phenomena are epigenetic. Epigenetic modifications, such as DNA methylation or histone marks, play key roles in genome function, and thus it is not surprising that the epigenetic landscape is under tight developmental regulation. However, recent evidence suggests that epigenetic profiles in mammals can be perturbed by environmental or stochastic factors. But could such epigenetic variants, or epialleles, be transmitted to subsequent generations? From a teleological perspective, epialleles should not be passed on to the next generation as they might interfere with key developmental programs. However, studies in mouse models show that epialleles occasionally escape the reprogramming events that occur during normal development, and thus persist in the cells of the offspring. If common, transgenerational epigenetic inheritance could have a significant impact on phenotypic outcomes. However, conclusive evidence of this phenomenon in humans is still lacking. To date, only three single-locus studies have claimed transgenerational epigenetic inheritance-like effects in humans, and even these have been controversial. We intend to perform the first-ever systematic genome-wide screen for transgenerational epigenetic inheritance in humans. The experimental design builds on substantial pilot data, and uses a systems-level approach that integrates a cohort of monozygotic twins and their offspring, genome-wide DNA methylation profiling, high-throughput sequencing, and bioinformatics. The results will yield crucial insights into the phenomenon of transgenerational epigenetic inheritance, thereby significantly impacting on our understanding of the biological basis of heritable phenotypes.

Summary

During the last 50 years, several studies have challenged the view that DNA is the sole biological unit of heredity in multi-cellular organisms such as mammals. In these studies, inter-individual phenotypic differences were observed that could not be explained by genetic or environmental heterogeneity and yet, surprisingly, were passed on to the offspring. We are now beginning to realize that the biological mechanisms at the heart of these phenomena are epigenetic. Epigenetic modifications, such as the addition of methyl groups to the DNA, occur naturally and stably influence genome function without changing the underlying DNA sequence. Specifically, epigenetic modifications play central roles in regulating gene expression, and therefore it is not surprising that the cell carefully controls when and where in the genome epigenetic modifications are established. However, recent evidence suggests that epigenetic modifications in mammals can be perturbed by environmental or stochastic factors, in some cases correlating with altered phenotypes in the individual. But could such epigenetic variants, be transmitted to the offspring? Theoretically, such epigenetic variants should not be passed on to the next generation as they might interfere with embryonic development of the offspring. Indeed, during normal mammalian development, epigenetic modifications are reprogrammed during early embryogenesis. However, studies in mouse models show that occasionally epigenetic variants escape this reprogramming event and persist in the cells of the offspring i.e. epigenetic inheritance - biological inheritance that is not encoded strictly in the DNA sequence. If common, epigenetic inheritance could have a significant impact on phenotypic outcomes in the context of both health and disease. However, conclusive evidence of this phenomenon in humans is still lacking. To date, only three single-gene studies have claimed transgenerational epigenetic inheritance-like effects in humans,and even these have been controversial. The main stumbling blocks have been access to: (i) suitable human cohorts in which epigenetic inheritance can be distinguished from the effects of genetics or environment; (ii) technologies for performing relatively unbiased experiments to search for these epigenetic variants. We intend to perform the first-ever systematic large-scale study of epigenetic inheritance in humans. The experimental design uses a powerful approach that integrates a cohort of identical twins and their offspring, cutting-edge genomics technologies, and custom computational biology methodologies. The results of our study will yield crucial insights into the phenomenon of epigenetic inheritance, thereby significantly impacting on our understanding of the biological basis of heritable phenotypic variation in humans.

Impact Summary

There is increasing evidence that epigenetic variation in human populations is more common than previously appreciated. In the short-term, the theoretical advances made by our research will benefit a broad range of researchers from a variety of disciplines within the UK and internationally will be interested in the results from our study. These will include researchers interested in: (i) Epigenetics (ii) Normal human phenotypes. (iii) Complex disease phenotypes (iv) The interaction of genetics and epigenetics (v) Environmental effects on genome function (vi) Reproductive Biology Furthermore, we expect our study to act as a blueprint for further investigations into the epigenetic basis of heritable phenotypic variation in human populations. Knowledge of the epigenetic basis of phenotypic variation will greatly enhance our understanding of the spectrum of influences on phenotypic outcomes. When integrated with knowledge of genetics and environment, our study will be beneficial for understanding both natural phenotypic variation in human populations and the causes of complex diseases. In the long-term, we can expect our results to indirectly impact on predictive and therapeutic strategies for combating the disease burden in human populations. Indeed, epigenetic-based strategies are already employed for some diseases e.g. cancer. The staff employed to work on this project will learn about epigenetics, bioinformatics, and genomics. All these disciplines are at the forefront of biological research and are already yielding novel and powerful biological insights and very recently, beginning to benefit human health. We will be generating genome-wide DNA methylation profiles from human tissues. We will adopt the appropriate standards for array data and take guidance from large data management centers such as the Wellcome Trust Sanger Institute, Cambridge, UK that are already handling datasets of the type we will be generating. All raw data will be accompanied by appropriate metadata needed to provide secondary users with the necessary details on the origin or manipulation of the data (e.g. non-confidential details on the samples used in the experiments, type of genomic information generated, any normalization/processing strategies, reasons for why any data were omitted from further analyses). The data will be a platform for follow-up studies in our labs and possibly collaborative efforts with other groups. The results will be disseminated via peer-reviewed publications, seminars at scientific conferences, and engagement with the general public.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Ageing
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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