Gavin Kelsey

Research Summary

It is thought that epigenetic information can be programmed by environmental factors, such as diet and early life experiences, and such changes can be perpetuated long after these exposures and potentially to future generations. Such epigenetic programming may contribute to our risk of developing disease in later life. Imprinted genes (whose expression is determined by the parent that contributed them) are a model for how epigenetic events in gametes of one generation dictate gene activity in the next.

Our mapping of methylation of DNA in the egg, sperm and embryo suggests that this epigenetic influence may extend well beyond the small number of known imprinted genes. Using genome-wide approaches, we are tracking the fate of DNA methylation patterns inherited from the egg and sperm, the stability of these marks throughout the lifetime and ageing, and how they affect activity of associated genes. In particular, we are investigating whether DNA methylation in particular populations of neurons in the hypothalamus, the part of the brain that senses nutritional status to control metabolism and appetite, is altered by exposure to altered diets and may modify response to nutritional status.

The discovery that gene transcription is essential for DNA methylation and imprint establishment may help to explain how the methylation modifications in the genome of the egg may be modified by adverse environments or how imprinting is disrupted in some imprinted gene disorders.

Latest Publications

Single-cell epigenomics: Recording the past and predicting the future.
Kelsey G, Stegle O, Reik W

Single-cell multi-omics has recently emerged as a powerful technology by which different layers of genomic output-and hence cell identity and function-can be recorded simultaneously. Integrating various components of the epigenome into multi-omics measurements allows for studying cellular heterogeneity at different time scales and for discovering new layers of molecular connectivity between the genome and its functional output. Measurements that are increasingly available range from those that identify transcription factor occupancy and initiation of transcription to long-lasting and heritable epigenetic marks such as DNA methylation. Together with techniques in which cell lineage is recorded, this multilayered information will provide insights into a cell's past history and its future potential. This will allow new levels of understanding of cell fate decisions, identity, and function in normal development, physiology, and disease.

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Science (New York, N.Y.), 358, 1095-9203, 69-75, 2017

PMID: 28983045

DNA Methylation in Embryo Development: Epigenetic Impact of ART (Assisted Reproductive Technologies).
Canovas S, Ross PJ, Kelsey G, Coy P

DNA methylation can be considered a component of epigenetic memory with a critical role during embryo development, and which undergoes dramatic reprogramming after fertilization. Though it has been a focus of research for many years, the reprogramming mechanism is still not fully understood. Recent results suggest that absence of maintenance at DNA replication is a major factor, and that there is an unexpected role for TET3-mediated oxidation of 5mC to 5hmC in guarding against de novo methylation. Base-resolution and genome-wide profiling methods are enabling more comprehensive assessments of the extent to which ART might impair DNA methylation reprogramming, and which sequence elements are most vulnerable. Indeed, as we also review here, studies showing the effect of culture media, ovarian stimulation or embryo transfer on the methylation pattern of embryos emphasize the need to face ART-associated defects and search for strategies to mitigate adverse effects on the health of ART-derived children.

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BioEssays : news and reviews in molecular, cellular and developmental biology, , 1521-1878, , 2017

PMID: 28940661

Genomic imprinting beyond DNA methylation: a role for maternal histones.
Hanna CW, Kelsey G

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Genome biology, 18, 1474-760X, 177, 2017

PMID: 28927436